The Experts below are selected from a list of 309 Experts worldwide ranked by ideXlab platform
Edward P. Acosta - One of the best experts on this subject based on the ideXlab platform.
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steady state amprenavir tenofovir and emtricitabine pharmacokinetics before and after reducing ritonavir boosting of a fosamprenavir tenofovir emtricitabine regimen from 200 mg to 100 mg once daily telex ii
Hiv Clinical Trials, 2009Co-Authors: David A Parks, Clay H Jennings, Christopher W Taylor, Gary E Pakes, Edward P. AcostaAbstract:AbstractPurpose: Evaluate how reducing ritonavir (RTV) boosting from 200 mg to 100 mg once daily (QD) affects steady-state pharmacokinetics of components of a fosamprenavir (FPV)-based regimen. Methods: Prospective, open-label, pharmacokinetic study in 12 HIV-infected patients stabilized on FPV/RTV 1400 mg/200 mg + tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) 300 mg/200 mg QD (TELEX II). Pharmacokinetics were assessed by noncompartmental analysis at baseline and 4 weeks after RTV reduction to 100 mg QD. Results: Baseline median Minimum Plasma Concentration (Cmin) and area under the Plasma Concentration-time curve over 24 hours post dose (AUC24h) were as follows: APV: 1,708 ng/mL, 84,260 h • ng/mL; tenofovir: 53 ng/mL, 2,420 h • ng/mL; FTC: 58 ng/mL, 9,190 h • ng/mL; RTV: 80 ng/mL, 10,230 h • ng/mL. Four weeks after reducing RTV, changes in Cmin and AUC24h were: APV: +26%, +0.6%; tenofovir: +77%, +30%; FTC: +188%, +13%; RTV –64%, –79%. Component Plasma Concentration ranges were consistent with h...
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Steady-state amprenavir, tenofovir, and emtricitabine pharmacokinetics before and after reducing ritonavir boosting of a fosamprenavir/tenofovir/emtricitabine regimen from 200 mg to 100 mg once daily (TELEX II).
HIV clinical trials, 2009Co-Authors: David A Parks, Christopher W Taylor, Gary E Pakes, H. Clay Jennings, Edward P. AcostaAbstract:AbstractPurpose: Evaluate how reducing ritonavir (RTV) boosting from 200 mg to 100 mg once daily (QD) affects steady-state pharmacokinetics of components of a fosamprenavir (FPV)-based regimen. Methods: Prospective, open-label, pharmacokinetic study in 12 HIV-infected patients stabilized on FPV/RTV 1400 mg/200 mg + tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) 300 mg/200 mg QD (TELEX II). Pharmacokinetics were assessed by noncompartmental analysis at baseline and 4 weeks after RTV reduction to 100 mg QD. Results: Baseline median Minimum Plasma Concentration (Cmin) and area under the Plasma Concentration-time curve over 24 hours post dose (AUC24h) were as follows: APV: 1,708 ng/mL, 84,260 h • ng/mL; tenofovir: 53 ng/mL, 2,420 h • ng/mL; FTC: 58 ng/mL, 9,190 h • ng/mL; RTV: 80 ng/mL, 10,230 h • ng/mL. Four weeks after reducing RTV, changes in Cmin and AUC24h were: APV: +26%, +0.6%; tenofovir: +77%, +30%; FTC: +188%, +13%; RTV –64%, –79%. Component Plasma Concentration ranges were consistent with h...
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Tipranavir
Clinical Pharmacokinetics, 2006Co-Authors: Jennifer R King, Edward P. AcostaAbstract:Tipranavir is a novel nonpeptidic protease inhibitor (PI) with activity against wild-type and multidrug-resistant HIV-1 both in vitro and in HIV-infected patients. Tipranavir/ritonavir 500mg/200mg administered twice daily for 3 weeks to healthy volunteers produced a median (range) maximum Plasma Concentration and Minimum Plasma Concentration of 79.1 (34.9–111.7) mg/L and 19.5 (0.43–42.8) mg/L, respectively. Concomitant administration with low-dose ritonavir significantly increases tipranavir Plasma Concentrations; therefore, the recommended dose is tipranavir 500mg and ritonavir 200mg twice daily. Tipranavir is a substrate and inducer of cytochrome P450 3A4 isoenzyme, thus is predisposed to interactions with other agents that are substrates, inducers or inhibitors of this enzyme family. Significant drug-drug interactions have been reported with co-administration of tipranavir/ritonavir and other PIs but not with the non-nucleoside reverse transcriptase inhibitors, efavirenz and nevirapine. Tipranavir/ritonavir 500mg/200mg twice daily in combination with an optimised background regimen was more effective than a ritonavir-boosted comparator PI plus an optimised background regimen. The adverse effect profile for tipranavir is similar to other boosted PI regimens and most commonly includes gastrointestinal complaints. Severe adverse events that require close monitoring include hepatotoxicity and lipid abnormalities. Tipranavir retains activity in many highly treatment-experienced patients with a large number of protease mutations. Therefore, this novel PI in combination with ritonavir represents an important new choice in the treatment of multiple-PI-experienced patients.
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tipranavir a novel nonpeptidic protease inhibitor of hiv
Clinical Pharmacokinectics, 2006Co-Authors: Jennifer R King, Edward P. AcostaAbstract:: Tipranavir is a novel nonpeptidic protease inhibitor (PI) with activity against wild-type and multidrug-resistant HIV-1 both in vitro and in HIV-infected patients. Tipranavir/ritonavir 500 mg/200 mg administered twice daily for 3 weeks to healthy volunteers produced a median (range) maximum Plasma Concentration and Minimum Plasma Concentration of 79.1 (34.9-111.7) mg/L and 19.5 (0.43-42.8) mg/L, respectively. Concomitant administration with low-dose ritonavir significantly increases tipranavir Plasma Concentrations; therefore, the recommended dose is tipranavir 500 mg and ritonavir 200 mg twice daily. Tipranavir is a substrate and inducer of cytochrome P450 3A4 isoenzyme, thus is predisposed to interactions with other agents that are substrates, inducers or inhibitors of this enzyme family. Significant drug-drug interactions have been reported with co-administration of tipranavir/ritonavir and other PIs but not with the non-nucleoside reverse transcriptase inhibitors, efavirenz and nevirapine. Tipranavir/ritonavir 500 mg/200 mg twice daily in combination with an optimised background regimen was more effective than a ritonavir-boosted comparator PI plus an optimised background regimen. The adverse effect profile for tipranavir is similar to other boosted PI regimens and most commonly includes gastrointestinal complaints. Severe adverse events that require close monitoring include hepatotoxicity and lipid abnormalities. Tipranavir retains activity in many highly treatment-experienced patients with a large number of protease mutations. Therefore, this novel PI in combination with ritonavir represents an important new choice in the treatment of multiple-PI-experienced patients.
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Practical implications for the interpretation of Minimum Plasma Concentration/inhibitory Concentration ratios.
Lancet (London England), 2001Co-Authors: Julio S. G. Montaner, Andrew Hill, Edward P. AcostaAbstract:For a drug to be clinically useful, Plasma Concentrations of the agent must achieve effective Concentrations. Logically, therefore, optimum administration of drugs includes selection of doses that provide adequate exposure. This approach has been successfully used during drug development—eg, for antibacterials 1 —and has been applied to agents used in the treatment of HIV-1. However, methods used to ascertain actual exposure, and targets for adequate exposure, to protease inhibitors, have not been standardised. This situation has resulted in confusion over the relevance of such tests in clinical practice. We review the procedures used, draw attention to the many variables involved in what can initially seem to be straightforward calculations, and emphasise the need for consistency to ensure that conclusions reached are scientifically accurate. We have illustrated this difficulty with HIV-1 protease inhibitors, however, the principles outlined are applicable to other therapies. Clinically effective Concentrations of antimicrobial drugs are difficult to predict, since potency is generally assessed in vitro (as inhibitory Concentration [IC]). For example, in HIV-1 infection, IC50 and IC90, the in-vitro Concentration of drug needed to inhibit viral replication by 50 or 90%, respectively, are cited most often. 2 The
Gérard Milano - One of the best experts on this subject based on the ideXlab platform.
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A Clinical Pharmacokinetic Analysis of Tegafur-Uracil (UFT) Plus Leucovorin Given in a New Twice-Daily Oral Administration Schedule
Clinical Pharmacokinetics, 2007Co-Authors: Marie-christine Etienne-grimaldi, Eric François, Jean-michel Cardot, Nicole Renée, Jean-yves Douillard, Erick Gamelin, Jaafar Bennouna, Yann Château, Gérard MilanoAbstract:Background and objective Tegafur is an oral fluorouracil prodrug used in the treatment of colorectal cancer. The aim of this phase II, crossover, bioequivalence study was to compare the pharmacokinetics (primary objective) and tolerability (secondary objective) of tegafur-uracil (UFT) given as three daily doses (tid, reference schedule) with those obtained using a more convenient schedule of two daily doses (bid, new schedule). Patient and methods Twenty-one patients with metastatic colorectal cancer (median age 63 years) received the same oral daily dose of UFT (300 mg/m^2/day) plus leucovorin (90 mg/day) divided into two or three daily doses. Patients were randomised to receive the first cycle either tid (12 patients) or bid (9 patients). The eligibility criteria included an Eastern Co-operative Oncology Group performance status of ≤1 and adequate bone-marrow, hepatic and renal function. The pharmacokinetics of uracil, fluorouracil and tegafur (high-performance liquid chromatography assays) were evaluated at steady state over 24 hours (area under the Plasma Concentration-time curve from 0 to 24 hours [AUC_24], Minimum Plasma Concentration [C_min] and maximum Plasma Concentration [C_max]). The pharmacokinetic parameters were analysed after logarithmic transformation according to a general linear model. Results The AUC_24 values of fluorouracil (p < 0.0001), uracil fp < 0.0001) and tegafur (p = 0.058) were greater with the bid schedule than the tid schedule. The bid: tid AUC24 ratio (90% CI) was 1.8 (1.55, 2.10) with fluorouracil, 2.0 (1.59, 2.57) with uracil and 1.2 (1.02, 1.36) with tegafur, indicating that the bid and tid schedules were not bioequivalent. No major toxicity (grade 4) was reported, and grade 3 adverse events accounted for 9% of the total adverse events. Intra-patient comparison of the maximum toxicity grade did not demonstrate a significant difference between the bid and tid schedules (p = 0.18). Conclusion A 2-fold increase in the fluorouracil and uracil AUC values was observed with UFT administered bid compared with tid, without a significant impact on tolerability, suggesting that the more convenient bid schedule may improve the UFT therapeutic index.
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A Clinical Pharmacokinetic Analysis of Tegafur-Uracil (UFT) Plus Leucovorin Given in a New Twice-Daily Oral Administration Schedule
Clinical Pharmacokinetics, 2007Co-Authors: Marie-christine Etienne-grimaldi, Eric François, Jean-michel Cardot, Nicole Renée, Jean-yves Douillard, Erick Gamelin, Jaafar Bennouna, Yann Château, Gérard MilanoAbstract:Background and objective Tegafur is an oral fluorouracil prodrug used in the treatment of colorectal cancer. The aim of this phase II, crossover, bioequivalence study was to compare the pharmacokinetics (primary objective) and tolerability (secondary objective) of tegafur-uracil (UFT) given as three daily doses (tid, reference schedule) with those obtained using a more convenient schedule of two daily doses (bid, new schedule). Patient and methods Twenty-one patients with metastatic colorectal cancer (median age 63 years) received the same oral daily dose of UFT (300 mg/m^2/day) plus leucovorin (90 mg/day) divided into two or three daily doses. Patients were randomised to receive the first cycle either tid (12 patients) or bid (9 patients). The eligibility criteria included an Eastern Co-operative Oncology Group performance status of ≤1 and adequate bone-marrow, hepatic and renal function. The pharmacokinetics of uracil, fluorouracil and tegafur (high-performance liquid chromatography assays) were evaluated at steady state over 24 hours (area under the Plasma Concentration-time curve from 0 to 24 hours [AUC_24], Minimum Plasma Concentration [C_min] and maximum Plasma Concentration [C_max]). The pharmacokinetic parameters were analysed after logarithmic transformation according to a general linear model. Results The AUC_24 values of fluorouracil (p < 0.0001), uracil fp < 0.0001) and tegafur (p = 0.058) were greater with the bid schedule than the tid schedule. The bid: tid AUC24 ratio (90% CI) was 1.8 (1.55, 2.10) with fluorouracil, 2.0 (1.59, 2.57) with uracil and 1.2 (1.02, 1.36) with tegafur, indicating that the bid and tid schedules were not bioequivalent. No major toxicity (grade 4) was reported, and grade 3 adverse events accounted for 9% of the total adverse events. Intra-patient comparison of the maximum toxicity grade did not demonstrate a significant difference between the bid and tid schedules (p = 0.18). Conclusion A 2-fold increase in the fluorouracil and uracil AUC values was observed with UFT administered bid compared with tid, without a significant impact on tolerability, suggesting that the more convenient bid schedule may improve the UFT therapeutic index.
Neeltje Steeghs - One of the best experts on this subject based on the ideXlab platform.
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Clinical Pharmacokinetics and Pharmacodynamics of the Cyclin-Dependent Kinase 4 and 6 Inhibitors Palbociclib, Ribociclib, and Abemaciclib.
Clinical pharmacokinetics, 2020Co-Authors: Stefanie L Groenland, Jos H Beijnen, Alwin D R Huitema, Alejandra Martínez-chávez, Alfred H. Schinkel, Marloes G. J. Van Dongen, Neeltje SteeghsAbstract:Palbociclib, ribociclib, and abemaciclib are inhibitors of the cyclin-dependent kinases 4 and 6 approved for the treatment of locally advanced or metastatic breast cancer. In this review, we provide an overview of the available clinical pharmacokinetic and pharmacodynamic characteristics of these novel drugs, summarize the results of food–effect and drug–drug interaction studies, and highlight exposure–response and exposure–toxicity relationships. All three drugs exhibit a large inter-individual variability in exposure (coefficient of variation range 40–95% for Minimum Plasma Concentration), are extensively metabolized by cytochrome P450 3A4, and have their brain penetration limited by efflux transporters. Abemaciclib has three active metabolites with similar potency that are clinically relevant (i.e., M2, M20, M18), whereas the metabolites of palbociclib and ribociclib are not of clinical significance. Pharmacokinetic exposure increases in a dose-proportional manner for palbociclib, whereas exposure increases under- and over-proportionally with an increasing dose for abemaciclib and ribociclib, respectively. High exposure is associated with an increased risk of neutropenia, and for ribociclib also to corrected QT prolongation. For abemaciclib, a clear exposure–efficacy relationship has been described, while for palbociclib and ribociclib exposure–response analyses remain inconclusive. Future studies are needed to address exposure–efficacy relationships to further improve dosing.
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concomitant intake of abiraterone acetate and food to increase pharmacokinetic exposure real life data from a therapeutic drug monitoring programme
European Journal of Cancer, 2020Co-Authors: Stefanie L Groenland, Merel Van Nuland, Andries M Bergman, Jeantine M De Feijter, Vincent O Dezentje, Hilde Rosing, Jos H Beijnen, Alwin D R Huitema, Neeltje SteeghsAbstract:Abstract Aim Abiraterone acetate is approved for the treatment of metastatic prostate cancer. At the currently used fixed dose of 1000 mg once daily in modified fasting state, 40% of patients do not reach the efficacy threshold of a Minimum Plasma Concentration (Cmin) ≥ 8.4 ng/mL and are thereby at risk of decreased treatment efficacy. This study aims to evaluate whether pharmacokinetically (PK) guided abiraterone acetate dosing with a food intervention is feasible and results in an increased percentage of patients with Concentrations above the target. Methods Patients starting regular treatment with abiraterone acetate in modified fasting state were included. Pharmacokinetic analysis was performed 4, 8 and 12 weeks after start of treatment and every 12 weeks thereafter. In case of Cmin Results In total, 32 evaluable patients were included, of which 20 patients (63%) had a Cmin Conclusion Therapeutic drug monitoring of abiraterone was applied in clinical practice and proved to be feasible. Concomitant intake with food resulted in a significant increase in Cmin and offers a cost-neutral opportunity to optimise exposure in patients with low Cmin.
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Therapeutic Drug Monitoring of Oral Anti-Hormonal Drugs in Oncology
Clinical Pharmacokinetics, 2019Co-Authors: Stefanie L Groenland, Merel Van Nuland, Jos H Beijnen, Alwin D R Huitema, Remy B. Verheijen, Jan H. M. Schellens, Neeltje SteeghsAbstract:Oral anti-hormonal drugs are essential in the treatment of breast and prostate cancer. It is well known that the interpatient variability in pharmacokinetic exposure is high for these agents and exposure–response relationships exist for many oral anti-hormonal drugs. Yet, they are still administered at fixed doses. This could lead to underdosing and thus suboptimal efficacy in some patients, while other patients could be overdosed resulting in unnecessary side effects. Therapeutic drug monitoring (TDM), individualized dosing based on measured blood Concentrations of the drug, could therefore be a valid option to further optimize treatment. In this review, we provide an overview of relevant clinical pharmacokinetic and pharmacodynamic characteristics of oral anti-hormonal drugs in oncology and translate these into practical guidelines for TDM. For some agents, TDM targets are not well established yet and as a reference the median pharmacokinetic exposure could be targeted (exemestane: Minimum Plasma Concentration ( C _min) 4.1 ng/mL and enzalutamide: C _min 11.4 mg/L). However, for most drugs, exposure–efficacy analyses could be translated into specific targets (abiraterone: C _min 8.4 ng/mL, anastrozole: C _min 34.2 ng/mL, and letrozole: C _min 85.6 ng/mL). Moreover, prospective clinical trials have shown TDM to be feasible for tamoxifen, for which the exposure–efficacy threshold of its active metabolite endoxifen is 5.97 ng/mL. Based on the available data, we therefore conclude that individualized dosing based on drug Concentrations is feasible and promising for oral anti-hormonal drugs and should be developed further and implemented into clinical practice.
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Exposure-response analyses of ALK-inhibitors crizotinib and alectinib in NSCLC patients
Annals of Oncology, 2019Co-Authors: Stefanie L Groenland, Jos H Beijnen, Alwin D R Huitema, Dieuwertje R Geel, Julie M Janssen, Egbert F. Smit, Sjaak Burgers, Neeltje SteeghsAbstract:Abstract Background Crizotinib and alectinib are first and second generation ALK-inhibitors, respectively, indicated for the treatment of ALK+ NSCLC. At the currently used fixed doses, interpatient variability in exposure is high (40%), while the registration studies suggest that exposure might be linked to efficacy (FDA Reviews). Therefore, the aim of this study was to explore whether exposure to crizotinib and alectinib is related to efficacy in a real life patient (pt) cohort. Methods A retrospective observational study was performed. ALK+ NSCLC pts who were treated with crizotinib or alectinib and of whom pharmacokinetic (PK) samples were drawn as part of routine care were included. Calculated Minimum Plasma Concentration (Cmin) was taken as a measure of exposure. Efficacy endpoint was progression free survival (PFS). Univariable and multivariable exposure-response analyses were performed using previously proposed thresholds of 235 µg/L for crizotinib and 435 µg/L for alectinib (Verheijen 2017). Variables taken into account were WHO performance status (PS) and previous lines of therapy for crizotinib, and WHO PS and previous treatment with ALK-inhibitors for alectinib. Results In total, 100 pts were included in this study (48 crizotinib, 52 alectinib), of whom 376 PK samples were eligible for analysis (235 crizotinib, 141 alectinib). Median number of samples per pt was 3 (range 1 – 15). Median Cmin per pt was 244 µg/L (IQR 176 – 344 µg/L) for crizotinib and 517 µg/L (IQR 369 – 659 µg/L) for alectinib. For crizotinib, median PFS was 5.7 vs 17.4 months (mo) for pts with median Cmin Conclusions This study shows that exposure to alectinib is associated with efficacy in a real life patient cohort. Therefore, therapeutic drug monitoring might be appropriate to individualize treatment and improve treatment outcomes. Legal entity responsible for the study Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital. Funding Has not received any funding. Disclosure S.A. Burgers: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Roche Advisory / Consultancy: MSD. N. Steeghs: Research grant / Funding (institution): AstraZeneca/MedImmune; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): AB Science; Research grant / Funding (institution): Deciphera; Research grant / Funding (institution): Merck Sharp & Dohme; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Merus; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Incyte. All other authors have declared no conflicts of interest.
David A Parks - One of the best experts on this subject based on the ideXlab platform.
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steady state amprenavir tenofovir and emtricitabine pharmacokinetics before and after reducing ritonavir boosting of a fosamprenavir tenofovir emtricitabine regimen from 200 mg to 100 mg once daily telex ii
Hiv Clinical Trials, 2009Co-Authors: David A Parks, Clay H Jennings, Christopher W Taylor, Gary E Pakes, Edward P. AcostaAbstract:AbstractPurpose: Evaluate how reducing ritonavir (RTV) boosting from 200 mg to 100 mg once daily (QD) affects steady-state pharmacokinetics of components of a fosamprenavir (FPV)-based regimen. Methods: Prospective, open-label, pharmacokinetic study in 12 HIV-infected patients stabilized on FPV/RTV 1400 mg/200 mg + tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) 300 mg/200 mg QD (TELEX II). Pharmacokinetics were assessed by noncompartmental analysis at baseline and 4 weeks after RTV reduction to 100 mg QD. Results: Baseline median Minimum Plasma Concentration (Cmin) and area under the Plasma Concentration-time curve over 24 hours post dose (AUC24h) were as follows: APV: 1,708 ng/mL, 84,260 h • ng/mL; tenofovir: 53 ng/mL, 2,420 h • ng/mL; FTC: 58 ng/mL, 9,190 h • ng/mL; RTV: 80 ng/mL, 10,230 h • ng/mL. Four weeks after reducing RTV, changes in Cmin and AUC24h were: APV: +26%, +0.6%; tenofovir: +77%, +30%; FTC: +188%, +13%; RTV –64%, –79%. Component Plasma Concentration ranges were consistent with h...
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Steady-state amprenavir, tenofovir, and emtricitabine pharmacokinetics before and after reducing ritonavir boosting of a fosamprenavir/tenofovir/emtricitabine regimen from 200 mg to 100 mg once daily (TELEX II).
HIV clinical trials, 2009Co-Authors: David A Parks, Christopher W Taylor, Gary E Pakes, H. Clay Jennings, Edward P. AcostaAbstract:AbstractPurpose: Evaluate how reducing ritonavir (RTV) boosting from 200 mg to 100 mg once daily (QD) affects steady-state pharmacokinetics of components of a fosamprenavir (FPV)-based regimen. Methods: Prospective, open-label, pharmacokinetic study in 12 HIV-infected patients stabilized on FPV/RTV 1400 mg/200 mg + tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) 300 mg/200 mg QD (TELEX II). Pharmacokinetics were assessed by noncompartmental analysis at baseline and 4 weeks after RTV reduction to 100 mg QD. Results: Baseline median Minimum Plasma Concentration (Cmin) and area under the Plasma Concentration-time curve over 24 hours post dose (AUC24h) were as follows: APV: 1,708 ng/mL, 84,260 h • ng/mL; tenofovir: 53 ng/mL, 2,420 h • ng/mL; FTC: 58 ng/mL, 9,190 h • ng/mL; RTV: 80 ng/mL, 10,230 h • ng/mL. Four weeks after reducing RTV, changes in Cmin and AUC24h were: APV: +26%, +0.6%; tenofovir: +77%, +30%; FTC: +188%, +13%; RTV –64%, –79%. Component Plasma Concentration ranges were consistent with h...
Gary E Pakes - One of the best experts on this subject based on the ideXlab platform.
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steady state amprenavir tenofovir and emtricitabine pharmacokinetics before and after reducing ritonavir boosting of a fosamprenavir tenofovir emtricitabine regimen from 200 mg to 100 mg once daily telex ii
Hiv Clinical Trials, 2009Co-Authors: David A Parks, Clay H Jennings, Christopher W Taylor, Gary E Pakes, Edward P. AcostaAbstract:AbstractPurpose: Evaluate how reducing ritonavir (RTV) boosting from 200 mg to 100 mg once daily (QD) affects steady-state pharmacokinetics of components of a fosamprenavir (FPV)-based regimen. Methods: Prospective, open-label, pharmacokinetic study in 12 HIV-infected patients stabilized on FPV/RTV 1400 mg/200 mg + tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) 300 mg/200 mg QD (TELEX II). Pharmacokinetics were assessed by noncompartmental analysis at baseline and 4 weeks after RTV reduction to 100 mg QD. Results: Baseline median Minimum Plasma Concentration (Cmin) and area under the Plasma Concentration-time curve over 24 hours post dose (AUC24h) were as follows: APV: 1,708 ng/mL, 84,260 h • ng/mL; tenofovir: 53 ng/mL, 2,420 h • ng/mL; FTC: 58 ng/mL, 9,190 h • ng/mL; RTV: 80 ng/mL, 10,230 h • ng/mL. Four weeks after reducing RTV, changes in Cmin and AUC24h were: APV: +26%, +0.6%; tenofovir: +77%, +30%; FTC: +188%, +13%; RTV –64%, –79%. Component Plasma Concentration ranges were consistent with h...
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Steady-state amprenavir, tenofovir, and emtricitabine pharmacokinetics before and after reducing ritonavir boosting of a fosamprenavir/tenofovir/emtricitabine regimen from 200 mg to 100 mg once daily (TELEX II).
HIV clinical trials, 2009Co-Authors: David A Parks, Christopher W Taylor, Gary E Pakes, H. Clay Jennings, Edward P. AcostaAbstract:AbstractPurpose: Evaluate how reducing ritonavir (RTV) boosting from 200 mg to 100 mg once daily (QD) affects steady-state pharmacokinetics of components of a fosamprenavir (FPV)-based regimen. Methods: Prospective, open-label, pharmacokinetic study in 12 HIV-infected patients stabilized on FPV/RTV 1400 mg/200 mg + tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) 300 mg/200 mg QD (TELEX II). Pharmacokinetics were assessed by noncompartmental analysis at baseline and 4 weeks after RTV reduction to 100 mg QD. Results: Baseline median Minimum Plasma Concentration (Cmin) and area under the Plasma Concentration-time curve over 24 hours post dose (AUC24h) were as follows: APV: 1,708 ng/mL, 84,260 h • ng/mL; tenofovir: 53 ng/mL, 2,420 h • ng/mL; FTC: 58 ng/mL, 9,190 h • ng/mL; RTV: 80 ng/mL, 10,230 h • ng/mL. Four weeks after reducing RTV, changes in Cmin and AUC24h were: APV: +26%, +0.6%; tenofovir: +77%, +30%; FTC: +188%, +13%; RTV –64%, –79%. Component Plasma Concentration ranges were consistent with h...
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amprenavir and lopinavir pharmacokinetics following coadministration of amprenavir or fosamprenavir with lopinavir ritonavir with or without efavirenz
Antiviral Therapy, 2007Co-Authors: Paul Pham, Craig W. Hendrix, Gary E Pakes, Patricia Barditchcrovo, Teresa L Parsons, Wasif Khan, Michelle Parish, Christine Radebaugh, Kathryn A Carson, Roula QaqishAbstract:BACKGROUND Amprenavir (APV), fosamprenavir (FPV), lopinavir (LPV), ritonavir (RTV) and efavirenz (EFV) are to varying degrees substrates, inducers and inhibitors of CYP3A4. Coadministration of these drugs might result in complex pharmacokinetic drug-drug interactions. METHODS Two prospective, open-label, non-randomized studies evaluated APV and LPV steady-state pharmacokinetics in HIV-infected patients on APV 750 mg twice daily + LPV/RTV 533/133 mg twice daily with EFV (n=7) or without EFV (n=12) + background nucleosides (Study 1) and after switching FPV 1,400 mg twice daily for APV (n=10) (Study 2). RESULTS In Study 1 EFV and non-EFV groups did not differ in APV Minimum Plasma Concentration (Cmin; 1.10 versus 1.06 microg/ml, P = 0.89), area under the Concentration-time curve (AUC; 17.46 versus 24.34 microg x h/ml, P = 0.22) or maximum Concentration (Cmax; 2.61 versus 4.33 microg/ml, P = 0.08); for LPV there was no difference in Cmin, (median: 3.66 versus 6.18 microg/ml, P = 0.20), AUC (81.84 versus 93.75 microg x h/ml, P = 0.37) or Cmax (10.36 versus 10.93 microg/ml, P = 0.61). In Study 2, after switching from APV to FPV, APV Cmin increased by 58% (0.83 versus 1.30 microg/ml, P = 0.0001), AUC by 76% (19.41 versus 34.24 micorg x h/ml, P = 0.0001), and Cmax by 75% (3.50 versus 6.14, P = 0.001). Compared with historical controls, LPV and RTV pharmacokinetics were not changed. All treatment regimens were well tolerated. Seven of eight completers (88%) maintained HIV-1 RNA <400 copies/ml 12 weeks after the switch (1 lost to follow up). CONCLUSIONS EFV did not appear to significantly alter APV and LPV pharmacokinetic parameters in HIV-infected patients taking APV 750 mg twice daily + LPV 533/133 mg twice daily. Switching FPV 1400 mg twice daily for APV 750 mg twice daily resulted in an increase in APV Cmin, AUC, and Cmax without changing LPV or RTV pharmacokinetics or overall tolerability.