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Roger J M Bruggemann - One of the best experts on this subject based on the ideXlab platform.
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Clinical Pharmacokinetics pharmacodynamics safety and efficacy of liposomal amphotericin b
Clinical Infectious Diseases, 2019Co-Authors: Andreas H Groll, Bart J A Rijnders, Thomas J Walsh, Jill Adlermoore, Russell E Lewis, Roger J M BruggemannAbstract:Since its introduction in the 1990s, liposomal amphotericin B (LAmB) continues to be an important agent for the treatment of invasive fungal diseases caused by a wide variety of yeasts and molds. This liposomal formulation was developed to improve the tolerability of intravenous amphotericin B, while optimizing its Clinical efficacy. Since then, numerous Clinical studies have been conducted, collecting a comprehensive body of evidence on its efficacy, safety, and tolerability in the preClinical and Clinical setting. Nevertheless, insights into the Pharmacokinetics and pharmacodynamics of LAmB continue to evolve and can be utilized to develop strategies that optimize efficacy while maintaining the compound's safety. In this article, we review the Clinical Pharmacokinetics, pharmacodynamics, safety, and efficacy of LAmB in a wide variety of patient populations and in different indications, and provide an assessment of areas with a need for further Clinical research.
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Clinical Pharmacokinetics and Pharmacodynamics of Micafungin
Clinical Pharmacokinetics, 2018Co-Authors: Roeland E. Wasmann, David M. Burger, Eline W. Muilwijk, Paul E. Verweij, Catherijne A. Knibbe, Roger J M BruggemannAbstract:Micafungin is a selective inhibitor of the synthesis of fungal 1,3-β- d -glucan, an essential component of the fungal cell wall. It is available as a powder for infusion only and is registered for the treatment of invasive and esophageal candidiasis in addition to prophylaxis of Candida infections in both adults and children. Average exposure after a single intravenous 100 mg dose in healthy adults is 133 mg h/L. Both exposure and maximum plasma concentration show linear dose proportional Pharmacokinetics (PK) over a 0.15–8 mg/kg dose range. In healthy adults, the clearance (CL) is 10.4 mL/h/kg and volume of distribution is 0.2 L/kg; both are independent of the dose. Micafungin is metabolized by arylsulfatase, catechol- O -methyltransferase, and several cytochrome P450 (CYP) isoenzymes (3A4, 1A2, 2B6 and 2C), but no dose adjustments are necessary in patients with (severe) hepatic dysfunction. Exposure to micafungin is lower in hematology patients, and is even further lowered in critically ill patients (including burn patients) compared with healthy volunteers, which might have consequences for treatment efficacy. In children, an increased CL has been reported: 40–80 mL/h/kg in premature neonates and 20 mL/h/kg in children >4 months of age. Therefore, relatively higher doses of 4–10 mg/kg in premature neonates and 2–4 mg/kg in children with invasive candidiasis are used. However, these higher CLs may also be explained by the eightfold higher free fraction of unbound micafungin in premature neonates, meaning that an augmented dose might not be required.
Henkjan Guchelaar - One of the best experts on this subject based on the ideXlab platform.
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Clinical Pharmacokinetics of tyrosine kinase inhibitors
Cancer Treatment Reviews, 2009Co-Authors: Nielka P Van Erp, Hans Gelderblom, Henkjan GuchelaarAbstract:In the recent years, eight tyrosine kinase inhibitors (TKIs) have been approved for cancer treatment and numerous are under investigation. These drugs are rationally designed to target specific tyrosine kinases that are mutated and/or over-expressed in cancer tissues. Post marketing study commitments have been made upon (accelerated) approval such as additional pharmacokinetic studies in patients with renal- or hepatic impairment, in children, additional interactions studies and studies on the relative or absolute bioavailability. Therefore, much information will emerge on the pharmacokinetic behavior of these drugs after their approval. In the present manuscript, the pharmacokinetic characteristics; absorption, distribution, metabolism and excretion (ADME), of the available TKIs are reviewed. Results from additional studies on the effect of drug transporters and drug-drug interactions have been incorporated. Overall, the TKIs reach their maximum plasma levels relatively fast; have an unknown absolute bioavailability, are extensively distributed and highly protein bound. The drugs are primarily metabolized by cytochrome P450 (CYP) 3A4 with other CYP-enzymes playing a secondary role. They are predominantly excreted with the feces and only a minor fraction is eliminated with the urine. All TKIs appear to be transported by the efflux ATP binding-cassette transports B1 and G2. Additionally these drugs can inhibit some of their own metabolizing enzymes and transporters making steady-state metabolism and drug-drug interactions both complex and unpredictable. By understanding the pharmacokinetic profile of these drugs and their similarities, factors that influence drug exposure will be better recognized and this knowledge may be used to limit sub- or supra-therapeutic drug exposure.
S E Tett - One of the best experts on this subject based on the ideXlab platform.
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mycophenolate Clinical Pharmacokinetics formulations and methods for assessing drug exposure
Transplantation Reviews, 2011Co-Authors: S E Tett, Christine E Staatz, Franck Saintmarcoux, Merce Brunet, Alexander A Vinks, Masatomo Miura, Pierre Marquet, Dirk Kuypers, Teun Van Gelder, Dario CattaneoAbstract:Abstract This article summarizes part of a consensus meeting about mycophenolate (MPA) therapeutic drug monitoring held in Rome under the auspices of The Transplantation Society in November 2008 ( Clin J Am Soc Nephrol . 2010;5:341–358). This part of the meeting focused on the Clinical Pharmacokinetics of MPA and included discussion on how to measure MPA (active drug) exposure and the differences between the currently available formulations. Summary points •Because of variability in the dose-concentration relationship, MPA exposure should be measured and doses should be adjusted accordingly to achieve optimal Clinical outcomes. •Suggested therapeutic exposures derived for MPA from mycophenolate mofetil (MMF) may differ to those that could be useful for MPA from enteric-coated mycophenolate sodium (EC-MPS), particularly if limited sampling strategies or single concentration, especially trough concentrations, is used, as the concentration-time profiles of MPA from the 2 formulations are quite different. The 2 MPA formulations cannot be considered as bioequivalent. •The area under the concentration-time curve (AUC 0–12 ) is considered the criterion standard for monitoring of MPA, which is a reflection of exposure to the drug over the entire dosing period. If a limited sampling protocol coupled with multilinear regression or Bayesian estimation is used to estimate this parameter, it should be used only for the population in which the model has been developed and should preferably include at least one time point after 4 hours (preferably around 8 or 9 hours after MMF dosing). If a single time point is to be used as a surrogate for an AUC 0–12 , trough concentration of MPA may be the most practical but, from a pharmacokinetic standpoint, is not the most informative time point to choose. •Because limited sampling strategies to estimate MPA exposure from EC-MPS have not yet been well developed and fully evaluated, nor have accurate Bayesian estimators been reported, AUC 0–12 measurement is still necessary to obtain reliable estimates of MPA exposure in patients treated with EC-MPS. The measurement of MPA trough concentrations should not be used at all for MPA exposure assessment following administration of EC-MPS. •Lower (or higher) than expected total MPA exposure in patients with severe renal impairment may still indicate sufficient free MPA exposure. Mycophenolate free exposure measurement/estimation is likely to be beneficial in patients with severe renal impairment (creatinine clearance •Lower total measured MPA exposure in patients with hypoalbuminemia may still indicate sufficient free MPA exposure. Mycophenolate free concentration measurement and estimation of exposure are likely to be beneficial in patients with a serum albumin less than or equal to 31 g/L to guide interpretation of MPA exposure. •A 1.5-g twice-daily starting dose of MMF rather than a 1-g twice-daily starting dose of MMF is more likely to achieve the minimum target MPA exposure in adult transplant recipients receiving concomitant cyclosporine therapy. Because the cyclosporine dose is progressively tapered following transplantation, MPA exposure should be measured repeatedly and MMF should be doses adjusted accordingly to achieve optimal Clinical outcome. •Mycophenolate exposure should be measured in the first week after transplant, then each week for the first month, each month until month 3, and subsequently every 3 months up to 1 year with appropriate dosage adjustment, as AUC is likely to increase over time. After 1 year, if dosage requirement has stabilized, MPA exposure can be assessed each time the immunosuppressive regimen is changed or a potentially interacting drug is introduced or withdrawn. •Assessment of UGT1A9 single nucleotide polymorphisms (−275T>A, −2152C>T, −440C>T, −331T>C) should be considered before transplantation to assist in dosing decisions to achieve optimal MPA exposure immediately after transplant. Consideration of the points summarized above should lead to more effective dosage adjustment based on sound applied pharmacokinetic and pharmacodynamic principles.
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Clinical Pharmacokinetics and pharmacodynamics of mycophenolate in solid organ transplant recipients
Clinical Pharmacokinectics, 2007Co-Authors: Christine E Staatz, S E TettAbstract:This review aims to provide an extensive overview of the literature on the Clinical Pharmacokinetics of mycophenolate in solid organ transplantation and a briefer summary of current pharmacodynamic information. Strategies are suggested for further optimisation of mycophenolate therapy and areas where additional research is warranted are highlighted. Mycophenolate has gained widespread acceptance as the antimetabolite immunosuppressant of choice in organ transplant regimens. Mycophenolic acid (MPA) is the active drug moiety.
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Clinical Pharmacokinetics and Pharmacodynamics of Mycophenolate in Solid Organ Transplant Recipients
Clinical Pharmacokinetics, 2007Co-Authors: Christine E Staatz, S E TettAbstract:This review aims to provide an extensive overview of the literature on the Clinical Pharmacokinetics of mycophenolate in solid organ transplantation and a briefer summary of current pharmacodynamic information. Strategies are suggested for further optimisation of mycophenolate therapy and areas where additional research is warranted are highlighted. Mycophenolate has gained widespread acceptance as the antimetabolite immunosuppressant of choice in organ transplant regimens. Mycophenolic acid (MPA) is the active drug moiety. Currently, two mycophenolate compounds are available, mycophenolate mofetil and enteric-coated (EC) mycophenolate sodium. MPA is a potent, selective and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), leading to eventual arrest of T- and B-lymphocyte proliferation. Mycophenolate mofetil and EC-mycophenolate sodium are essentially completely hydrolysed to MPA by esterases in the gut wall, blood, liver and tissue. Oral bioavailability of MPA, subsequent to mycophenolate mofetil administration, ranges from 80.7% to 94%. EC-mycophenolate sodium has an absolute bioavailability of MPA of approximately 72%. MPA binds 97–99% to serum albumin in patients with normal renal and liver function. It is metabolised in the liver, gastrointestinal tract and kidney by uridine diphosphate gluconosyltransferases (UGTs). 7- O -MPA-glucuronide (MPAG) is the major metabolite of MPA. MPAG is usually present in the plasma at 20- to 100-fold higher concentrations than MPA, but it is not pharmacologically active. At least three minor metabolites are also formed, of which an acyl-glucuronide has pharmacological potency comparable to MPA. MPAG is excreted into the urine via active tubular secretion and into the bile by multi-drug resistance protein 2 (MRP-2). MPAG is de-conjugated back to MPA by gut bacteria and then reabsorbed in the colon. Mycophenolate mofetil and EC-mycophenolate sodium display linear Pharmacokinetics. Following mycophenolate mofetil administration, MPA maximum concentration usually occurs in 1–2 hours. EC-mycophenolate sodium exhibits a median lag time in absorption of MPA from 0.25 to 1.25 hours. A secondary peak in the concentration-time profile of MPA, due to enterohepatic recirculation, often appears 6–12 hours after dosing. This contributes approximately 40% to the area under the plasma concentration-time curve (AUC). The mean elimination half-life of MPA ranges from 9 to 17 hours. MPA displays large between- and within-subject pharmacokinetic variability. Dose-normalised MPA AUC can vary more than 10-fold. Total MPA concentrations should be interpreted with caution in patients with severe renal impairment, liver disease and hypoalbuminaemia. In such individuals, MPA and MPAG plasma protein binding may be altered, changing the fraction of free MPA available. Apparent oral clearance (CL/F) of total MPA appears to increase in proportion to the increased free fraction, with a reduction in total MPA AUC. However, there may be little change in the MPA free concentration. Ciclosporin inhibits biliary excretion of MPAG by MRP-2, reducing enterohepatic recirculation of MPA. Exposure to MPA when mycophenolate mofetil is given in combination with ciclosporin is approximately 30–40% lower than when given alone or with tacrolimus or sirolimus. High dosages of corticosteroids may induce expression of UGT, reducing exposure to MPA. Other co-medications can interfere with the absorption, enterohepatic recycling and metabolism of mycophenolate. Most pharmacokinetic investigations of MPA have involved mycophenolate mofetil rather than EC-mycophenolate sodium therapy. In population pharmacokinetic studies, MPA CL/F in adults ranges from 14.1 to 34.9 L/h (ciclosporin co-therapy) and from 11.9 to 25.4 L/h (tacrolimus co-therapy). Patient bodyweight, serum albumin concentration and immunosuppressant co-therapy have a significant influence on CL/F. The majority of pharmacodynamic data on MPA have been obtained in patients receiving mycophenolate mofetil therapy in the first year after kidney transplantation. Low MPA AUC is associated with increased incidence of biopsy-proven acute rejection. Gastrointestinal adverse events may be dose related. Leukopenia and anaemia have been associated with high MPA AUC, trough concentration and metabolite concentrations in some, but not all, studies. High free MPA exposure has been identified as a risk factor for leukopenia in some investigations. Targeting a total MPA AUC from 0 to 12 hours (AUC12) of 30–60 mg ∙ hr/L is likely to minimise the risk of acute rejection and may reduce toxicity. IMPDH monitoring is in the early experimental stage. Individualisation of mycophenolate therapy should lead to improved patient outcomes. MPA AUC12 appears to be the most useful exposure measure for such individualisation. Limited sampling strategies and Bayesian forecasting are practical means of estimating MPA AUC12 without full concentration-time profiling. Target concentration intervention may be particularly useful in the first few months post-transplant and prior to major changes in anti-rejection therapy. In patients with impaired renal or hepatic function or hypoalbuminaemia, free drug measurement could be valuable in further interpretation of MPA exposure.
Andreas H Groll - One of the best experts on this subject based on the ideXlab platform.
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Clinical Pharmacokinetics pharmacodynamics safety and efficacy of liposomal amphotericin b
Clinical Infectious Diseases, 2019Co-Authors: Andreas H Groll, Bart J A Rijnders, Thomas J Walsh, Jill Adlermoore, Russell E Lewis, Roger J M BruggemannAbstract:Since its introduction in the 1990s, liposomal amphotericin B (LAmB) continues to be an important agent for the treatment of invasive fungal diseases caused by a wide variety of yeasts and molds. This liposomal formulation was developed to improve the tolerability of intravenous amphotericin B, while optimizing its Clinical efficacy. Since then, numerous Clinical studies have been conducted, collecting a comprehensive body of evidence on its efficacy, safety, and tolerability in the preClinical and Clinical setting. Nevertheless, insights into the Pharmacokinetics and pharmacodynamics of LAmB continue to evolve and can be utilized to develop strategies that optimize efficacy while maintaining the compound's safety. In this article, we review the Clinical Pharmacokinetics, pharmacodynamics, safety, and efficacy of LAmB in a wide variety of patient populations and in different indications, and provide an assessment of areas with a need for further Clinical research.
Luisa Sambati - One of the best experts on this subject based on the ideXlab platform.
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Clinical Pharmacokinetics of pramipexole ropinirole and rotigotine in patients with parkinson s disease
Parkinsonism & Related Disorders, 2019Co-Authors: Manuela Contin, Giovanna Lopane, Susan Mohamed, Giovanna Calandrabuonaura, Sabina Capellari, Patrizia De Massis, Stefania Nassetti, Alessandro Perrone, Roberto Riva, Luisa SambatiAbstract:Abstract Introduction Pramipexole (PRA), ropinirole (ROP) and rotigotine (ROT) are non-ergoline dopaminergic agonists (DAs) used to treat Parkinson's disease (PD). Clinical Pharmacokinetics of DAs is poorly characterized in PD. The main purpose of our study was to investigate the effect of dose, age and sex on steady-state plasma concentrations of DAs in real life PD patients on chronic DAs therapy. Methods The study was single center, open and prospective. Blood samples for measurement of DAs plasma concentrations were drawn in the morning, at a median 18-h distance from the last DA dose. Results Ninety-one patients treated with PRA, 50 with ROP and 37 with ROT were enrolled in the study. Plasma concentration of DAs significantly correlated with weight-adjusted daily dose in all subgroups, although at a given dose, matched plasma concentrations highly varied among patients. Median PRA plasma concentration-to-daily dose ratio (C/D) [(ng/mL)/(mg/kg/d)] was 68% higher in patients >65 years than ≤65 years (158 vs 94, p Conclusion These are the first observations on DAs Pharmacokinetics in PD patients’ everyday Clinical practice. Of relevance, patients over 65yrs may require about one third of PRA dose compared to under 65yrs to achieve the same plasma concentration. Due to the high intersubject variability in plasma concentrations at the same dosage, we speculate that monitoring of plasma DAs might be helpful in the individualization of treatment in selected patients.