The Experts below are selected from a list of 15459 Experts worldwide ranked by ideXlab platform
Craig R. Rayner - One of the best experts on this subject based on the ideXlab platform.
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Population Pharmacokinetics of Oseltamivir: Pediatrics through Geriatrics
Antimicrobial agents and chemotherapy, 2013Co-Authors: Mohamed A. Kamal, Craig R. Rayner, Scott A. Van Wart, Vishak Subramoney, Daniel K. Reynolds, Catharine C. Bulik, Patrick F. Smith, Sujata M. Bhavnani, Paul G. Ambrose, Alan ForrestAbstract:Oseltamivir is a potent inhibitor of influenza virus neuraminidase enzymes essential for viral replication. This study aimed to investigate the impact of covariates on pharmacokinetic (PK) variability of Oseltamivir and its active metabolite form, Oseltamivir carboxylate (OC). Dosing history, plasma drug concentrations, and demographic information were pooled from 13 clinical trials providing data for 390 healthy and infected subjects ranging in age from 1 to 78 years and given Oseltamivir doses of 20 to 1,000 mg. Candidate population PK models simultaneously characterizing the time course of Oseltamivir and OC in plasma were evaluated by using the NONMEM software program, and subject covariates were assessed using stepwise forward selection (α = 0.01) and backward elimination (α = 0.001). A two-compartment model with first-order absorption of Oseltamivir and first-order conversion of Oseltamivir to OC and a one-compartment model with first-order elimination of OC were utilized. Body weight when evaluated using a power function was a significant predictor of the apparent Oseltamivir clearance and both apparent OC clearance (CLm/F) and central volume of distribution (Vcm/F). Creatinine clearance was a significant predictor of CLm/F, while Vcm/F also decreased linearly with age. A visual predictive check indicated that the final model described Oseltamivir and OC concentrations in plasma adequately across dose regimens and subject covariate ranges. Concordance of population mean and individual post hoc predictions of maximum concentration of drug at steady state (Cmax) and area under the plasma drug concentration-time curve from 0 to 24 h at steady state (AUC0–24) was high (r2 = 0.81 and 0.71, respectively). In conclusion, a comprehensive population PK model was constructed to bridge the adult to pediatric Oseltamivir PK data, allowing for reasonable estimation of the PK of OC using subject demographic data alone.
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role of the intestinal peptide transporter pept1 in Oseltamivir absorption in vitro and in vivo studies
Drug Metabolism and Disposition, 2012Co-Authors: Agnes Poirier, Craig R. Rayner, Christoph Funk, Michael B. Otteneder, Eric Prinssen, Sara Belli, Renee Portmann, Katja Heinig, Stanley E LazicAbstract:It was reported that Oseltamivir (Tamiflu) absorption was mediated by human peptide transporter (hPEPT) 1. Understanding the exact mechanism(s) of absorption is important in the context of drug-drug and diet-drug interactions. Hence, we investigated the mechanism governing the intestinal absorption of Oseltamivir and its active metabolite (Oseltamivir carboxylate) in wild-type [Chinese hamster ovary (CHO)-K1] and hPEPT1-transfected cells (CHO-PEPT1), in pharmacokinetic studies in juvenile and adult rats, and in healthy volunteers. In vitro cell culture studies showed that the intracellular accumulation of Oseltamivir and its carboxylate into CHO-PEPT1 and CHO-K1 was always similar under a variety of experimental conditions, demonstrating that these compounds are not substrates of hPEPT1. Furthermore, neither Oseltamivir nor its active metabolite was capable of inhibiting Gly-Sar uptake in CHO-PEPT1 cells. In vivo pharmacokinetic studies in juvenile and adult rats showed that the disposition of Oseltamivir and Oseltamivir carboxylate, after oral administration of Oseltamivir, was sensitive to the feed status but insensitive to the presence of milk and Gly-Sar. Moreover, Oseltamivir and Oseltamivir carboxylate exhibited significantly higher exposure in rats under fasted conditions than under fed conditions. In humans, oral dosing after a high-fat meal resulted in a statistically significant but moderate lower exposure than after an overnight fasting. This change has no clinical implications. Taken together, the results do not implicate either rat Pept1 or hPEPT1 in the oral absorption of Oseltamivir.
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Oseltamivir in seasonal, pandemic, and avian influenza: a comprehensive review of 10-years clinical experience
Advances in Therapy, 2011Co-Authors: James R. Smith, Craig R. Rayner, Barbara Donner, Martina Wollenhaupt, Klaus Klumpp, Regina DutkowskiAbstract:Oseltamivir (Tamiflu®; F. Hoffmann-La Roche Ltd, Basel, Switzerland) is an orally administered antiviral for the treatment and prevention of influenza A and B infections that is registered in more than 100 countries worldwide. More than 83 million patients have been exposed to the product since its introduction. Oseltamivir is recommended by the World Health Organization (WHO) for use in the clinical management of pandemic and seasonal influenza of varying severity, and as the primary antiviral agent for treatment of avian H5N1 influenza infection in humans. This article is a nonsystematic review of the experience gained from the first 10 years of using Oseltamivir for influenza infections since its launch in early 2000, emphasizing recent advances in our understanding of the product and its clinical utility in five main areas. The article reviews the pharmacokinetics of Oseltamivir and its active metabolite, Oseltamivir carboxylate, including information on special populations such as children and elderly adults, and the co-administration of Oseltamivir with other agents. This is followed by a summary of data on the effectiveness of Oseltamivir treatment and prophylaxis in patients with all types of influenza, including pandemic (H1N1) 2009 and avian H5N1 influenza. The implications of changes in susceptibility of circulating influenza viruses to Oseltamivir and other antiviral agents are also described, as is the emergence of antiviral resistance during and after the 2009 pandemic. The fourth main section deals with the safety profile of Oseltamivir in standard and special patient populations, and reviews spontaneously reported adverse event data from the pandemic and pre-pandemic periods and the topical issue of neuropsychiatric adverse events. Finally, the article considers the pharmacoeconomics of Oseltamivir in comparison with vaccination and usual care regimens, and as a component of pandemic influenza mitigation strategies.
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Nonclinical Pharmacokinetics of Oseltamivir and Oseltamivir Carboxylate in the Central Nervous System
Antimicrobial agents and chemotherapy, 2009Co-Authors: Gerhard Hoffmann, Craig R. Rayner, Christoph Funk, Stephen Fowler, Michael B. Otteneder, Alexander Breidenbach, Tom Chu, Eric PrinssenAbstract:Oseltamivir, a potent and selective inhibitor of influenza A and B virus neuraminidases, is a prodrug that is systemically converted into the active metabolite Oseltamivir carboxylate. In light of reported neuropsychiatric events in influenza patients, including some taking Oseltamivir, and as part of a full assessment to determine whether Oseltamivir could contribute to, or exacerbate, such events, we undertook a series of nonclinical studies. In particular, we investigated (i) the distribution of Oseltamivir and Oseltamivir carboxylate in the central nervous system of rats after single intravenous doses of Oseltamivir and Oseltamivir carboxylate and oral doses of Oseltamivir, (ii) the active transport of Oseltamivir and Oseltamivir carboxylate in vitro by transporters located in the blood-brain barrier, and (iii) the extent of local conversion of Oseltamivir to Oseltamivir carboxylate in brain fractions. In all experiments, results showed that the extent of partitioning of Oseltamivir and especially Oseltamivir carboxylate to the central nervous system was low. Brain-to-plasma exposure ratios were approximately 0.2 for Oseltamivir and 0.01 for Oseltamivir carboxylate. Apart from Oseltamivir being a good substrate for the P-glycoprotein transporter, no other active transport processes were observed. The conversion of the prodrug to the active metabolite was slow and limited in human and rat brain S9 fractions. Overall, these studies indicate that the potential for Oseltamivir and Oseltamivir carboxylate to reach the central nervous system in high quantities is low and, together with other analyses and studies, that their involvement in neuropsychiatric events in influenza patients is unlikely.
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population pharmacokinetics of Oseltamivir when coadministered with probenecid
The Journal of Clinical Pharmacology, 2008Co-Authors: Craig R. Rayner, Pascal Chanu, Ronald Gieschke, Lauren Boak, Niclas E JonssonAbstract:Oseltamivir is a potent, selective, oral neuraminidase inhibitor for the treatment and prophylaxis of influenza. Plasma concentrations of the active metabolite, Oseltamivir carboxylate, are increased in the presence of probenecid, suggesting that the combination could allow for the use of reduced doses of Oseltamivir. To investigate this proposal, we developed a population pharmacokinetic model and simulated the pharmacokinetics of candidate combination regimens of oral Oseltamivir (45 mg and 30 mg twice a day) plus oral probenecid (500 mg/6 hourly). Probenecid plus Oseltamivir 45 mg achieved all the pharmacokinetic parameters expected of Oseltamivir alone, but combination with Oseltamivir 30 mg and dose interval extension approaches did not. An Oseltamivir-probenecid combination may compromise tolerability and enhance the potential for drug interactions. In addition, increased dosing requirements may affect compliance and attainment of optimal Oseltamivir exposure, potentially facilitating the emergence of viral strains with reduced susceptibility to Oseltamivir. These factors, set alongside increased capacity for Oseltamivir production, should be carefully considered before an Oseltamivir-probenecid combination is used.
Regina Dutkowski - One of the best experts on this subject based on the ideXlab platform.
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Oseltamivir in seasonal, pandemic, and avian influenza: a comprehensive review of 10-years clinical experience
Advances in Therapy, 2011Co-Authors: James R. Smith, Craig R. Rayner, Barbara Donner, Martina Wollenhaupt, Klaus Klumpp, Regina DutkowskiAbstract:Oseltamivir (Tamiflu®; F. Hoffmann-La Roche Ltd, Basel, Switzerland) is an orally administered antiviral for the treatment and prevention of influenza A and B infections that is registered in more than 100 countries worldwide. More than 83 million patients have been exposed to the product since its introduction. Oseltamivir is recommended by the World Health Organization (WHO) for use in the clinical management of pandemic and seasonal influenza of varying severity, and as the primary antiviral agent for treatment of avian H5N1 influenza infection in humans. This article is a nonsystematic review of the experience gained from the first 10 years of using Oseltamivir for influenza infections since its launch in early 2000, emphasizing recent advances in our understanding of the product and its clinical utility in five main areas. The article reviews the pharmacokinetics of Oseltamivir and its active metabolite, Oseltamivir carboxylate, including information on special populations such as children and elderly adults, and the co-administration of Oseltamivir with other agents. This is followed by a summary of data on the effectiveness of Oseltamivir treatment and prophylaxis in patients with all types of influenza, including pandemic (H1N1) 2009 and avian H5N1 influenza. The implications of changes in susceptibility of circulating influenza viruses to Oseltamivir and other antiviral agents are also described, as is the emergence of antiviral resistance during and after the 2009 pandemic. The fourth main section deals with the safety profile of Oseltamivir in standard and special patient populations, and reviews spontaneously reported adverse event data from the pandemic and pre-pandemic periods and the topical issue of neuropsychiatric adverse events. Finally, the article considers the pharmacoeconomics of Oseltamivir in comparison with vaccination and usual care regimens, and as a component of pandemic influenza mitigation strategies.
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Oseltamivir in seasonal influenza: cumulative experience in low- and high-risk patients
Journal of Antimicrobial Chemotherapy, 2010Co-Authors: Regina DutkowskiAbstract:Seasonal influenza viruses cause annual disease epidemics that affect individuals at low and high risk for secondary illnesses. Influenza vaccines are widely used in high-risk patients to prevent infection, but the protection afforded varies by population; uptake is also limited in some groups. Antiviral drugs for influenza are now readily available. Oseltamivir is the most widely used antiviral for the treatment and prophylaxis of seasonal influenza, and its efficacy and safety are now well established in a variety of populations. In addition to decreasing the severity and duration of the symptoms of influenza, clinical and epidemiological studies demonstrate that Oseltamivir significantly reduces the frequency of secondary illnesses and exacerbation of underlying conditions; survival is also significantly improved in seriously ill patients who are hospitalized with severe influenza. Resistant viruses are isolated with a low frequency during Oseltamivir treatment (0.33% in adults and 4.0% in children among almost 2000 Oseltamivir-treated patients enrolled onto Roche-sponsored clinical trials of Oseltamivir treatment during the Oseltamivir development programme). However, an Oseltamivir-resistant influenza A (H1N1) virus emerged in Europe during the 2007-08 season and circulated in the southern and northern hemispheres in 2008-09. No link with Oseltamivir usage could be detected, and the clinical impact of these viruses was limited. Oseltamivir-susceptible pandemic (H1N1) 2009 viruses now predominate in many countries. Oseltamivir is generally well tolerated, with a similar adverse event profile to placebo.
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Assessment of Neuropsychiatric Adverse Events in Influenza Patients Treated with Oseltamivir
Drug Safety, 2008Co-Authors: Stephen Toovey, Gerhard Hoffmann, Alexander Breidenbach, Eric Prinssen, Barbara Donner, Bharat Thakrar, Regina Dutkowski, Lothar Lindemann, Craig Rayner, Ellen CareyAbstract:After reports from Japan of neuropsychiatric adverse events (NPAEs) in children taking Oseltamivir phosphate (hereafter referred to as Oseltamivir [Tamiflu®; F. Hoffmann-La Roche Ltd, Basel, Switzerland]) during and after the 2004–5 influenza season, Roche explored possible reasons for the increase in reporting rate and presented regular updates to the US FDA and other regulatory authorities. This review summarizes the results of a comprehensive assessment of the company’s own preclinical and clinical studies, post-marketing spontaneous adverse event reporting, epidemiological investigations utilizing health claims and medical records databases and an extensive review of the literature, with the aim of answering the following questions: (i) what the types and rates of neuropsychiatric abnormalities reported in patients with influenza are, and whether these differ in patients who have received Oseltamivir compared with those who have not; (ii) what levels of Oseltamivir and its active metabolite, Oseltamivir carboxylate are achieved in the CNS; (iii) whether Oseltamivir and Oseltamivircarboxylate have pharmacological activity in the CNS; and (iv) whether there are genetic differences between Japanese and Caucasian patients that result in different levels of Oseltamivir and/or Oseltamivir carboxylate in the CNS, differences in their metabolism or differences in their pharmacological activity in the CNS. In total, 3051 spontaneous reports of NPAEs were received by Roche, involving 2466 patients who received Oseltamivir between 1999 and 15 September 2007; 2772 (90.9%) events originated from Japan, 190 (6.2%) from the US and 89 (2.9%) from other countries. During this period, Oseltamivir was prescribed to around 48 million people worldwide. Crude NPAE reporting rates (per 1 000 000 prescriptions) in children (aged ≤16 years) and adults, respectively, were 99 and 28 events in Japan and 19 and 8 in the US. NPAEs were more commonly reported in children (2218 events in 1808 children aged >16 years vs 833 in 658 adults) and generally occurred within 48 hours of the onset of influenza illness and initiation of treatment. After categorizing the reported events according to International Classification of Diseases (9th edition) codes, abnormal behaviour (1160 events, 38.0%) and delusions/perceptual disturbances (661 events, 21.7%) were the largest categories of events, and delirium or delirium-like events (as defined by the American Psychiatric Association) were very common in most categories. No difference in NPAE reporting rates between Oseltamivir and placebo was found in phase III treatment studies (0.5% vs 0.6%). Analyses of US healthcare claims databases showed the risk of NPAEs in Oseltamivir-treated patients (n =159 386) was no higher than those not receiving antivirals (n = 159 386). Analysis of medical records in the UK General Practice Research Database showed that the adjusted relative risk of NPAEs in influenza patients was significantly higher (1.75-fold) than in the general population. Based on literature reports, NPAEs in Japanese and Taiwanese children with influenza have occurred before the initiation of Oseltamivir treatment; events were also similar to those occurring after the initiation of Oseltamivir therapy. No clinically relevant differences in plasma pharmacokinetics of Oseltamivir and its active metabolite Oseltamivir carboxylate were noted between Japanese and Caucasian adults or children. Penetration into the CNS of both Oseltamivir and Oseltamivir carboxylate was low in Japanese and Caucasian adults (cerebrospinal fluid/plasma maximum concentration and area under the plasma concentration-time curve ratios of approximately 0.03), and the capacity for converting Oseltamivir to Oseltamivir carboxylate in rat and human brains was low. In animal autoradiography and pharmacokinetic studies, brain: plasma radioactivity ratios were generally 20% or lower. Animal studies showed no specific CNS/behavioural effects after administration of doses corresponding to ≥100 times the clinical dose. Oseltamivir or Oseltamivir carboxylate did not interact with human neuraminidases or with 155 known molecular targets in radioligand binding and functional assays. A review of the information published to date on functional variations of genes relevant to Oseltamivir pharmacokinetics and pharmacodynamics and simulated gene knock-out scenarios did not identify any plausible genetic explanations for the observed NPAEs. The available data do not suggest that the incidence of NPAEs in influenza patients receiving Oseltamivir is higher than in those who do not, and no mechanism by which Oseltamivir or Oseltamivir carboxylate could cause or worsen such events could be identified.
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assessment of neuropsychiatric adverse events in influenza patients treated with Oseltamivir a comprehensive review
Drug Safety, 2008Co-Authors: Stephen Toovey, Craig R. Rayner, Gerhard Hoffmann, Alexander Breidenbach, Tom Chu, Eric Prinssen, Barbara Donner, Bharat Thakrar, Regina Dutkowski, Lothar LindemannAbstract:After reports from Japan of neuropsychiatric adverse events (NPAEs) in children taking Oseltamivir phosphate (hereafter referred to as Oseltamivir [Tamiflu; F. Hoffmann-La Roche Ltd, Basel, Switzerland]) during and after the 2004--5 influenza season, Roche explored possible reasons for the increase in reporting rate and presented regular updates to the US FDA and other regulatory authorities. This review summarizes the results of a comprehensive assessment of the company's own preclinical and clinical studies, post-marketing spontaneous adverse event reporting, epidemiological investigations utilizing health claims and medical records databases and an extensive review of the literature, with the aim of answering the following questions: (i) what the types and rates of neuropsychiatric abnormalities reported in patients with influenza are, and whether these differ in patients who have received Oseltamivir compared with those who have not; (ii) what levels of Oseltamivir and its active metabolite, Oseltamivir carboxylate are achieved in the CNS; (iii) whether Oseltamivir and Oseltamivir carboxylate have pharmacological activity in the CNS; and (iv) whether there are genetic differences between Japanese and Caucasian patients that result in different levels of Oseltamivir and/or Oseltamivir carboxylate in the CNS, differences in their metabolism or differences in their pharmacological activity in the CNS. In total, 3051 spontaneous reports of NPAEs were received by Roche, involving 2466 patients who received Oseltamivir between 1999 and 15 September 2007; 2772 (90.9%) events originated from Japan, 190 (6.2%) from the US and 89 (2.9%) from other countries. During this period, Oseltamivir was prescribed to around 48 million people worldwide. Crude NPAE reporting rates (per 1,000,000 prescriptions) in children (aged or =100 times the clinical dose. Oseltamivir or Oseltamivir carboxylate did not interact with human neuraminidases or with 155 known molecular targets in radioligand binding and functional assays. A review of the information published to date on functional variations of genes relevant to Oseltamivir pharmacokinetics and pharmacodynamics and simulated gene knock-out scenarios did not identify any plausible genetic explanations for the observed NPAEs. The available data do not suggest that the incidence of NPAEs in influenza patients receiving Oseltamivir is higher than in those who do not, and no mechanism by which Oseltamivir or Oseltamivir carboxylate could cause or worsen such events could be identified. Language: en
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safety and pharmacology of Oseltamivir in clinical use
Drug Safety, 2003Co-Authors: Regina Dutkowski, Hara Thakra, Enrico Froehlich, Pia Sute, Penny WardAbstract:Oseltamivir is a novel agent approved for the treatment and prevention of influenza infection and illnesses in adults and children. Assessment of data from the clinical trial programme, a US health insurance database study and postmarketing surveillance allowed a comprehensive review of the safety of Oseltamivir in clinical use in subjects >1 year of age. Oseltamivir has been studied over the course of a 5-year development programme in >11000 subjects from North America, Europe and the Southern Hemisphere, including otherwise healthy adults, approximately 500 elderly/high-risk subjects, and children (>1000) aged 1-12 years. Safety evaluations included treatment-emergent adverse events, hospitalisations and deaths, as well as haematological and biochemical laboratory safety tests. The data reveals that Oseltamivir has simple, uncomplicated pharmacology and lacks potential for drug-drug interactions. Electrocardiogram parameters, including corrected QT interval, were unaffected by Oseltamivir even at high doses. Postmarketing studies confirmed that transient gastrointestinal disturbance is the major adverse effect of Oseltamivir and that this can be reduced by taking Oseltamivir after a light snack. On treatment serious adverse events were reported in 1.3% of Oseltamivir 75mg twice daily, 0.7% of Oseltamivir 150 mg twice daily and 1.2% of placebo recipients, respectively, in the clinical trial programme. Postmarketing, it is estimated that, to date, over 4 million Oseltamivir prescriptions have been dispensed worldwide. Approximately 2300 spontaneous reports were received by the manufacturer over the three winter seasons of use. As these events are reported infrequently and from an unknown number of users, it is not possible to definitively assess causality or frequency of reported events. Most reports were of gastrointestinal and skin reactions. However, a clear association between the skin reactions and Oseltamivir has not been established. A large study of insurance records, which permitted the assessment of the relative risk of medical events treated in the month following prescription of Oseltamivir in general use, showed no evidence of increased risk of cardiac, neuropsychiatric or respiratory events for those receiving Oseltamivir compared with those who did not. To conclude, no important safety concerns have evolved which might limit the suitability of Oseltamivir for the treatment and prevention of influenza in all patient populations.
Eric Prinssen - One of the best experts on this subject based on the ideXlab platform.
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role of the intestinal peptide transporter pept1 in Oseltamivir absorption in vitro and in vivo studies
Drug Metabolism and Disposition, 2012Co-Authors: Agnes Poirier, Craig R. Rayner, Christoph Funk, Michael B. Otteneder, Eric Prinssen, Sara Belli, Renee Portmann, Katja Heinig, Stanley E LazicAbstract:It was reported that Oseltamivir (Tamiflu) absorption was mediated by human peptide transporter (hPEPT) 1. Understanding the exact mechanism(s) of absorption is important in the context of drug-drug and diet-drug interactions. Hence, we investigated the mechanism governing the intestinal absorption of Oseltamivir and its active metabolite (Oseltamivir carboxylate) in wild-type [Chinese hamster ovary (CHO)-K1] and hPEPT1-transfected cells (CHO-PEPT1), in pharmacokinetic studies in juvenile and adult rats, and in healthy volunteers. In vitro cell culture studies showed that the intracellular accumulation of Oseltamivir and its carboxylate into CHO-PEPT1 and CHO-K1 was always similar under a variety of experimental conditions, demonstrating that these compounds are not substrates of hPEPT1. Furthermore, neither Oseltamivir nor its active metabolite was capable of inhibiting Gly-Sar uptake in CHO-PEPT1 cells. In vivo pharmacokinetic studies in juvenile and adult rats showed that the disposition of Oseltamivir and Oseltamivir carboxylate, after oral administration of Oseltamivir, was sensitive to the feed status but insensitive to the presence of milk and Gly-Sar. Moreover, Oseltamivir and Oseltamivir carboxylate exhibited significantly higher exposure in rats under fasted conditions than under fed conditions. In humans, oral dosing after a high-fat meal resulted in a statistically significant but moderate lower exposure than after an overnight fasting. This change has no clinical implications. Taken together, the results do not implicate either rat Pept1 or hPEPT1 in the oral absorption of Oseltamivir.
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Nonclinical Pharmacokinetics of Oseltamivir and Oseltamivir Carboxylate in the Central Nervous System
Antimicrobial agents and chemotherapy, 2009Co-Authors: Gerhard Hoffmann, Craig R. Rayner, Christoph Funk, Stephen Fowler, Michael B. Otteneder, Alexander Breidenbach, Tom Chu, Eric PrinssenAbstract:Oseltamivir, a potent and selective inhibitor of influenza A and B virus neuraminidases, is a prodrug that is systemically converted into the active metabolite Oseltamivir carboxylate. In light of reported neuropsychiatric events in influenza patients, including some taking Oseltamivir, and as part of a full assessment to determine whether Oseltamivir could contribute to, or exacerbate, such events, we undertook a series of nonclinical studies. In particular, we investigated (i) the distribution of Oseltamivir and Oseltamivir carboxylate in the central nervous system of rats after single intravenous doses of Oseltamivir and Oseltamivir carboxylate and oral doses of Oseltamivir, (ii) the active transport of Oseltamivir and Oseltamivir carboxylate in vitro by transporters located in the blood-brain barrier, and (iii) the extent of local conversion of Oseltamivir to Oseltamivir carboxylate in brain fractions. In all experiments, results showed that the extent of partitioning of Oseltamivir and especially Oseltamivir carboxylate to the central nervous system was low. Brain-to-plasma exposure ratios were approximately 0.2 for Oseltamivir and 0.01 for Oseltamivir carboxylate. Apart from Oseltamivir being a good substrate for the P-glycoprotein transporter, no other active transport processes were observed. The conversion of the prodrug to the active metabolite was slow and limited in human and rat brain S9 fractions. Overall, these studies indicate that the potential for Oseltamivir and Oseltamivir carboxylate to reach the central nervous system in high quantities is low and, together with other analyses and studies, that their involvement in neuropsychiatric events in influenza patients is unlikely.
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Assessment of Neuropsychiatric Adverse Events in Influenza Patients Treated with Oseltamivir
Drug Safety, 2008Co-Authors: Stephen Toovey, Gerhard Hoffmann, Alexander Breidenbach, Eric Prinssen, Barbara Donner, Bharat Thakrar, Regina Dutkowski, Lothar Lindemann, Craig Rayner, Ellen CareyAbstract:After reports from Japan of neuropsychiatric adverse events (NPAEs) in children taking Oseltamivir phosphate (hereafter referred to as Oseltamivir [Tamiflu®; F. Hoffmann-La Roche Ltd, Basel, Switzerland]) during and after the 2004–5 influenza season, Roche explored possible reasons for the increase in reporting rate and presented regular updates to the US FDA and other regulatory authorities. This review summarizes the results of a comprehensive assessment of the company’s own preclinical and clinical studies, post-marketing spontaneous adverse event reporting, epidemiological investigations utilizing health claims and medical records databases and an extensive review of the literature, with the aim of answering the following questions: (i) what the types and rates of neuropsychiatric abnormalities reported in patients with influenza are, and whether these differ in patients who have received Oseltamivir compared with those who have not; (ii) what levels of Oseltamivir and its active metabolite, Oseltamivir carboxylate are achieved in the CNS; (iii) whether Oseltamivir and Oseltamivircarboxylate have pharmacological activity in the CNS; and (iv) whether there are genetic differences between Japanese and Caucasian patients that result in different levels of Oseltamivir and/or Oseltamivir carboxylate in the CNS, differences in their metabolism or differences in their pharmacological activity in the CNS. In total, 3051 spontaneous reports of NPAEs were received by Roche, involving 2466 patients who received Oseltamivir between 1999 and 15 September 2007; 2772 (90.9%) events originated from Japan, 190 (6.2%) from the US and 89 (2.9%) from other countries. During this period, Oseltamivir was prescribed to around 48 million people worldwide. Crude NPAE reporting rates (per 1 000 000 prescriptions) in children (aged ≤16 years) and adults, respectively, were 99 and 28 events in Japan and 19 and 8 in the US. NPAEs were more commonly reported in children (2218 events in 1808 children aged >16 years vs 833 in 658 adults) and generally occurred within 48 hours of the onset of influenza illness and initiation of treatment. After categorizing the reported events according to International Classification of Diseases (9th edition) codes, abnormal behaviour (1160 events, 38.0%) and delusions/perceptual disturbances (661 events, 21.7%) were the largest categories of events, and delirium or delirium-like events (as defined by the American Psychiatric Association) were very common in most categories. No difference in NPAE reporting rates between Oseltamivir and placebo was found in phase III treatment studies (0.5% vs 0.6%). Analyses of US healthcare claims databases showed the risk of NPAEs in Oseltamivir-treated patients (n =159 386) was no higher than those not receiving antivirals (n = 159 386). Analysis of medical records in the UK General Practice Research Database showed that the adjusted relative risk of NPAEs in influenza patients was significantly higher (1.75-fold) than in the general population. Based on literature reports, NPAEs in Japanese and Taiwanese children with influenza have occurred before the initiation of Oseltamivir treatment; events were also similar to those occurring after the initiation of Oseltamivir therapy. No clinically relevant differences in plasma pharmacokinetics of Oseltamivir and its active metabolite Oseltamivir carboxylate were noted between Japanese and Caucasian adults or children. Penetration into the CNS of both Oseltamivir and Oseltamivir carboxylate was low in Japanese and Caucasian adults (cerebrospinal fluid/plasma maximum concentration and area under the plasma concentration-time curve ratios of approximately 0.03), and the capacity for converting Oseltamivir to Oseltamivir carboxylate in rat and human brains was low. In animal autoradiography and pharmacokinetic studies, brain: plasma radioactivity ratios were generally 20% or lower. Animal studies showed no specific CNS/behavioural effects after administration of doses corresponding to ≥100 times the clinical dose. Oseltamivir or Oseltamivir carboxylate did not interact with human neuraminidases or with 155 known molecular targets in radioligand binding and functional assays. A review of the information published to date on functional variations of genes relevant to Oseltamivir pharmacokinetics and pharmacodynamics and simulated gene knock-out scenarios did not identify any plausible genetic explanations for the observed NPAEs. The available data do not suggest that the incidence of NPAEs in influenza patients receiving Oseltamivir is higher than in those who do not, and no mechanism by which Oseltamivir or Oseltamivir carboxylate could cause or worsen such events could be identified.
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low penetration of Oseltamivir and its carboxylate into cerebrospinal fluid in healthy japanese and caucasian volunteers
Antimicrobial Agents and Chemotherapy, 2008Co-Authors: S S Jhee, Gerhard Hoffmann, Lauren Boak, Mark Yen, L Ereshefsky, M T Leibowitz, M Schulte, B Kaeser, A Patel, Eric PrinssenAbstract:Oseltamivir is a potent, well-tolerated antiviral for the treatment and prophylaxis of influenza. Although no relationship with treatment could be demonstrated, recent reports of abnormal behavior in young individuals with influenza who were receiving Oseltamivir have generated renewed interest in the central nervous system (CNS) tolerability of Oseltamivir. This single-center, open-label study explored the pharmacokinetics of Oseltamivir and Oseltamivir carboxylate (OC) in the plasma and cerebrospinal fluid (CSF) of healthy adult volunteers over a 24-hour interval to determine the CNS penetration of both these compounds. Four Japanese and four Caucasian males were enrolled in the study. Oseltamivir and OC concentrations in CSF were low (mean of observed maximum concentrations [Cmax], 2.4 ng/ml [Oseltamivir] and 19.0 ng/ml [OC]) versus those in plasma (mean Cmax, 115 ng/ml [Oseltamivir] and 544 ng/ml [OC]), with corresponding Cmax CSF/plasma ratios of 2.1% (Oseltamivir) and 3.5% (OC). Overall exposure to Oseltamivir and OC in CSF was also comparatively low versus that in plasma (mean area under the concentration-time curve CSF/plasma ratio, 2.4% [Oseltamivir] and 2.9% [OC]). No gross differences in the pharmacokinetics of Oseltamivir or OC were observed between the Japanese and Caucasian subjects. Oseltamivir was well tolerated. This demonstrates that the CNS penetration of Oseltamivir and OC is low in Japanese and Caucasian adults. Emerging data support the idea that Oseltamivir and OC have limited potential to induce or exacerbate CNS adverse events in individuals with influenza. A disease- rather than drug-related effect appears likely.
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assessment of neuropsychiatric adverse events in influenza patients treated with Oseltamivir a comprehensive review
Drug Safety, 2008Co-Authors: Stephen Toovey, Craig R. Rayner, Gerhard Hoffmann, Alexander Breidenbach, Tom Chu, Eric Prinssen, Barbara Donner, Bharat Thakrar, Regina Dutkowski, Lothar LindemannAbstract:After reports from Japan of neuropsychiatric adverse events (NPAEs) in children taking Oseltamivir phosphate (hereafter referred to as Oseltamivir [Tamiflu; F. Hoffmann-La Roche Ltd, Basel, Switzerland]) during and after the 2004--5 influenza season, Roche explored possible reasons for the increase in reporting rate and presented regular updates to the US FDA and other regulatory authorities. This review summarizes the results of a comprehensive assessment of the company's own preclinical and clinical studies, post-marketing spontaneous adverse event reporting, epidemiological investigations utilizing health claims and medical records databases and an extensive review of the literature, with the aim of answering the following questions: (i) what the types and rates of neuropsychiatric abnormalities reported in patients with influenza are, and whether these differ in patients who have received Oseltamivir compared with those who have not; (ii) what levels of Oseltamivir and its active metabolite, Oseltamivir carboxylate are achieved in the CNS; (iii) whether Oseltamivir and Oseltamivir carboxylate have pharmacological activity in the CNS; and (iv) whether there are genetic differences between Japanese and Caucasian patients that result in different levels of Oseltamivir and/or Oseltamivir carboxylate in the CNS, differences in their metabolism or differences in their pharmacological activity in the CNS. In total, 3051 spontaneous reports of NPAEs were received by Roche, involving 2466 patients who received Oseltamivir between 1999 and 15 September 2007; 2772 (90.9%) events originated from Japan, 190 (6.2%) from the US and 89 (2.9%) from other countries. During this period, Oseltamivir was prescribed to around 48 million people worldwide. Crude NPAE reporting rates (per 1,000,000 prescriptions) in children (aged or =100 times the clinical dose. Oseltamivir or Oseltamivir carboxylate did not interact with human neuraminidases or with 155 known molecular targets in radioligand binding and functional assays. A review of the information published to date on functional variations of genes relevant to Oseltamivir pharmacokinetics and pharmacodynamics and simulated gene knock-out scenarios did not identify any plausible genetic explanations for the observed NPAEs. The available data do not suggest that the incidence of NPAEs in influenza patients receiving Oseltamivir is higher than in those who do not, and no mechanism by which Oseltamivir or Oseltamivir carboxylate could cause or worsen such events could be identified. Language: en
Joel Tarning - One of the best experts on this subject based on the ideXlab platform.
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Population pharmacokinetics of Oseltamivir and Oseltamivir carboxylate in obese and non‐obese volunteers
British journal of clinical pharmacology, 2016Co-Authors: Kalayanee Chairat, Warunee Hanpithakpong, Sasithon Pukrittayakamee, Nicholas J. White, Podjanee Jittamala, Nicholas P. J. Day, Joel TarningAbstract:Aims The aims of the present study were to compare the pharmacokinetics of Oseltamivir and its active antiviral metabolite Oseltamivir carboxylate in obese and non-obese individuals and to determine the effect of obesity on the pharmacokinetic properties of Oseltamivir and Oseltamivir carboxylate. Methods The population pharmacokinetic properties of Oseltamivir and Oseltamivir carboxylate were evaluated in 12 obese [body mass index (BMI) ≥30 kg m−2) and 12 non-obese (BMI
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Comparison of Oseltamivir and Oseltamivir Carboxylate Concentrations in Venous Plasma, Venous Blood, and Capillary Blood in Healthy Volunteers
Antimicrobial agents and chemotherapy, 2013Co-Authors: Insti Instiaty, Niklas Lindegardh, Podjanee Jittmala, Warunee Hanpithakpong, Daniel Blessborn, Sasithon Pukrittayakamee, Nicholas J. White, Joel TarningAbstract:Oseltamivir and Oseltamivir carboxylate concentrations were measured in venous plasma, venous blood, and capillary blood taken simultaneously from 24 healthy volunteers. Median (range) venous-blood-to-plasma ratios were 1.42 (0.920 to 1.97) for Oseltamivir and 0.673 (0.564 to 0.814) for Oseltamivir carboxylate. Capillary blood/venous plasma ratios were 1.32 (0.737 to 3.16) for Oseltamivir and 0.685 (0.502 to 1.34) for Oseltamivir carboxylate. Oseltamivir concentrations in venous and capillary blood were similar. Oseltamivir carboxylate showed a time-dependent distribution between venous and capillary blood.
Bruce A Mueller - One of the best experts on this subject based on the ideXlab platform.
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association of Oseltamivir activation with gender and carboxylesterase 1 genetic polymorphisms
Basic & Clinical Pharmacology & Toxicology, 2016Co-Authors: Jian Shi, Rachel F Eyler, Bruce A Mueller, Xinwen Wang, Yan Liang, Li Liu, Hao Jie ZhuAbstract:Oseltamivir, an inactive anti-influenza virus prodrug, is activated (hydrolysed) in vivo by carboxylesterase 1 (CES1) to its active metabolite Oseltamivir carboxylate. CES1 functions are significantly associated with certain CES1 genetic variants and some non-genetic factors. The purpose of this study was to investigate the effect of gender and several CES1 genetic polymorphisms on Oseltamivir activation using a large set of individual human liver samples. CES1-mediated Oseltamivir hydrolysis and CES1 genotypes, including the G143E (rs71647871), rs2244613, rs8192935, the -816A>C (rs3785161) and the CES1P1/CES1P1VAR, were determined in 104 individual human livers. The results showed that hepatic CES1 protein expression in females was 17.3% higher than that in males (p = 0.039), while Oseltamivir activation rate in the livers from female donors was 27.8% higher than that from males (p = 0.076). As for CES1 genetic polymorphisms, neither CES1 protein expression nor CES1 activity on Oseltamivir activation was significantly associated with the rs2244613, rs8192935, -816A>C or CES1P1/CES1P1VAR genotypes. However, Oseltamivir hydrolysis in the livers with the genotype 143G/E was approximately 40% of that with the 143G/G genotype (0.7 ± 0.2 versus 1.8 ± 1.1 nmole/mg protein/min, p = 0.005). In summary, the results suggest that hepatic Oseltamivir activation appears to be more efficient in females than that in males, and the activation can be impaired by functional CES1 variants, such as the G143E. However, clinical implication of CES1 gender differences and pharmacogenetics in Oseltamivir pharmacotherapy warrants further investigations.
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Pharmacokinetics of Oseltamivir and Oseltamivir carboxylate in critically ill patients receiving continuous venovenous hemodialysis and/or extracorporeal membrane oxygenation.
Pharmacotherapy, 2012Co-Authors: Rachel F Eyler, Michael Heung, Melissa Pleva, Kevin M Sowinski, Pauline K Park, Lena M Napolitano, Bruce A MuellerAbstract:tudy Objective To investigate Oseltamivir and Oseltamivir carboxylate pharmacokinetics in critically ill patients who were receiving continuous venovenous hemodialysis (CVVHD) and/or extracorporeal membrane oxygenation (ECMO). Design Prospective, open-label, pharmacokinetic study. Setting Intensive care units of an academic medical center. Patients Thirteen critically ill patients aged 13 years or older with suspected or confirmed H1N1 influenza who had a prescription for Oseltamivir and were concurrently receiving CVVHD and/or ECMO between October 2009 and January 2010. Intervention Oseltamivir 150 mg was administered nasogastrically or nasoenterically every 12 hours. Blood samples were collected at baseline and at 1, 2, 4, 6, 8, 10, and 12 hours after administration of the fourth Oseltamivir dose or subsequent doses. In patients receiving CVVHD, effluent also was collected at the same time points. Urine was collected throughout the 12-hour dosing interval. Measurements and Main Results Eight patients received CVVHD only, four patients received both CVVHD and ECMO, and one patient received ECMO only. Pharmacokinetic parameters for the patient who received only ECMO were not reported. The median maximum plasma concentration and area under the plasma concentration–time curve for the 12-hour dosing interval (AUC0–12) for the remaining 12 patients were 83.4 ng/ml and 216 ng•hour/ml, respectively, for Oseltamivir and 2000 ng/ml and 21,500 ng•hour/ml, respectively, for Oseltamivir carboxylate. Mean clearance due to CVVHD was 33.8 ml/minute for Oseltamivir and 50.2 ml/minute for Oseltamivir carboxylate. For patients who received ECMO, no substantial differences between pre- and post-ECMO oxygenator plasma concentrations were found for Oseltamivir or Oseltamivir carboxylate. Conclusion Although the optimal pharmacokinetic-pharmacodynamic targets for Oseltamivir carboxylate remain unclear, in the patients receiving CVVHD with or without ECMO, a regimen of Oseltamivir 150 mg every 12 hours yielded a median Oseltamivir carboxylate AUC0–12 considerably higher than would be expected in non–critically ill patients receiving the same dosage regimen.
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pharmacokinetics of Oseltamivir and Oseltamivir carboxylate in critically ill patients receiving continuous venovenous hemodialysis and or extracorporeal membrane oxygenation
Pharmacotherapy, 2012Co-Authors: Rachel F Eyler, Michael Heung, Melissa Pleva, Kevin M Sowinski, Pauline K Park, Lena M Napolitano, Bruce A MuellerAbstract:tudy Objective To investigate Oseltamivir and Oseltamivir carboxylate pharmacokinetics in critically ill patients who were receiving continuous venovenous hemodialysis (CVVHD) and/or extracorporeal membrane oxygenation (ECMO). Design Prospective, open-label, pharmacokinetic study. Setting Intensive care units of an academic medical center. Patients Thirteen critically ill patients aged 13 years or older with suspected or confirmed H1N1 influenza who had a prescription for Oseltamivir and were concurrently receiving CVVHD and/or ECMO between October 2009 and January 2010. Intervention Oseltamivir 150 mg was administered nasogastrically or nasoenterically every 12 hours. Blood samples were collected at baseline and at 1, 2, 4, 6, 8, 10, and 12 hours after administration of the fourth Oseltamivir dose or subsequent doses. In patients receiving CVVHD, effluent also was collected at the same time points. Urine was collected throughout the 12-hour dosing interval. Measurements and Main Results Eight patients received CVVHD only, four patients received both CVVHD and ECMO, and one patient received ECMO only. Pharmacokinetic parameters for the patient who received only ECMO were not reported. The median maximum plasma concentration and area under the plasma concentration–time curve for the 12-hour dosing interval (AUC0–12) for the remaining 12 patients were 83.4 ng/ml and 216 ng•hour/ml, respectively, for Oseltamivir and 2000 ng/ml and 21,500 ng•hour/ml, respectively, for Oseltamivir carboxylate. Mean clearance due to CVVHD was 33.8 ml/minute for Oseltamivir and 50.2 ml/minute for Oseltamivir carboxylate. For patients who received ECMO, no substantial differences between pre- and post-ECMO oxygenator plasma concentrations were found for Oseltamivir or Oseltamivir carboxylate. Conclusion Although the optimal pharmacokinetic-pharmacodynamic targets for Oseltamivir carboxylate remain unclear, in the patients receiving CVVHD with or without ECMO, a regimen of Oseltamivir 150 mg every 12 hours yielded a median Oseltamivir carboxylate AUC0–12 considerably higher than would be expected in non–critically ill patients receiving the same dosage regimen.
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the pharmacokinetics of Oseltamivir and Oseltamivir carboxylate in a critically ill pediatric patient receiving extracorporeal membrane oxygenation and continuous venovenous hemodialysis
The journal of pediatric pharmacology and therapeutics : JPPT, 2012Co-Authors: Rachel F Eyler, Kristin C Klein, Bruce A MuellerAbstract:This report details the pharmacokinetics of Oseltamivir and Oseltamivir carboxylate following administration of high-dose Oseltamivir in a critically ill child receiving extracorporeal membrane oxygenation (ECMO) and continuous venovenous hemodialysis (CVVHD). A 6-year-old critically ill male patient suffering from a presumed viral illness was transferred to our institution’s pediatric intensive care unit from an outside hospital after developing respiratory failure and cardiomegaly. ECMO and Oseltamivir therapy were initiated upon admission, and CVVHD was started on hospital day 3. Pharmacokinetic sampling occurred at an Oseltamivir dose of approximately 4 mg/kg on hospital day 6. The patient’s Oseltamivir and Oseltamivir carboxylate area under the plasma concentration time curves for the 12-hour dosing interval (AUC0–12) were 30.5 and 905 ng/mLhr, respectively. Drug clearance by CVVHD was 31.6 mL/min for Oseltamivir and 26.9 mL/min for Oseltamivir carboxylate. Pre- and postoxygenator Oseltamivir and Oseltamivir carboxylate plasma concentrations did not differ substantially. The patient’s Oseltamivir carboxylate plasma concentrations remained well above the reported mean 50% inhibitory concentration for 2009 pandemic H1N1 virus. However, despite receiving twice the standard dose of Oseltamivir, the Oseltamivir carboxylate AUC0–12 in our patient was less than that reported in noncritically ill pediatric subjects. The reduced Oseltamivir carboxylate AUC0–12 found in our patient was most likely due to decreased drug absorption.