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Pharmacokinetics, Food Effect, Ketoconazole Interaction, and Safety of JTK-853, a Novel Nonnucleoside HCV Polymerase Inhibitor, After Ascending Single and Multiple Doses in Healthy Subjects.
Tamaki, S, Shibata, T, Hunt, T, Gerhardt, B, Yamada, H, Pai, SM
Clinical pharmacology in drug development. 2019;(3):371-384
Abstract
Pharmacokinetics, safety, and tolerability of JTK-853, a novel HCV polymerase inhibitor, were evaluated in single and multiple ascending dose (SAD, MAD) studies, with food- and ketoconazole-related effects on exposure to JTK-853 and its active (CYP3A4 mediated) metabolite M2. JTK-853 was safe and well tolerated in both studies. In the SAD study, at doses >1600 mg (with standard breakfast [SBF]), JTK-853 exposure did not increase further, was substantially higher (AUCinf increase: 3- to 8-fold) with SBF (vs fasted), with a moderate increase in AUCinf (approximately 1.5-fold [1600 mg]) with a high-fat breakfast (vs SBF). In the SAD study (400-1600 mg, SBF), mean effective half-life (t1/2(eff) ) of JTK-853 was 8.3 to 10.9 hours, and 20.3 to 27.3 hours in the MAD study (twice daily dosing, fed condition), with 2- to 3-fold accumulation in exposure (AUCtau ). At steady-state, AUCtau increased dose proportionally, and was approximately 2-fold higher with ketoconazole coadministration. Metabolite M2 (equipotent to JTK-853 in vitro) did not contribute significantly to parent drug exposure and decreased with increase in dose, repeated dosing, and ketoconazole coadministration. Trial simulation-based ratios (n = 1000/dose level) of trough JTK-853 plasma concentrations to the in vitro EC90 for HCV genotype 1b were assessed for dose selection in a separate proof-of-concept study in patients. The studies enabled delineation of key drug attributes for further assessments in the target population.
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Effect of ketoconazole, a strong CYP3A inhibitor, on the pharmacokinetics of venetoclax, a BCL-2 inhibitor, in patients with non-Hodgkin lymphoma.
Agarwal, SK, Salem, AH, Danilov, AV, Hu, B, Puvvada, S, Gutierrez, M, Chien, D, Lewis, LD, Wong, SL
British journal of clinical pharmacology. 2017;(4):846-854
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Abstract
AIMS: To examine the effect of a strong cytochrome P450 (CYP) 3A inhibitor, ketoconazole, on the pharmacokinetics, safety and tolerability of venetoclax. METHODS Twelve patients with non-Hodgkin lymphoma (NHL) were enrolled in this Phase 1, open-label, fixed-sequence study. Patients received a single 50 mg dose of venetoclax orally on Day 1 and Day 8, and a 400 mg once daily dose of ketoconazole on Days 5-11. Blood samples were collected predose and up to 96 h after each venetoclax dose on Day 1 and Day 8. RESULTS Eleven patients had evaluable pharmacokinetic data and were therefore included in the statistical analyses. Compared to administration of a single 50 mg dose of venetoclax alone, ketoconazole increased the venetoclax mean maximum observed plasma concentration (Cmax ) and area under the plasma concentration-time curve from time 0 to infinity (AUC∞ ) by 2.3-fold (90% confidence interval [CI]: 2.0-2.7) and 6.4-fold (90% CI: 4.5-9.2; range: 2- to 12-fold), respectively. CONCLUSIONS Coadministration of venetoclax with multiple doses of ketoconazole resulted in a significant increase of venetoclax exposures, strongly suggesting that CYP3A plays a major role in elimination of venetoclax in patients. These results suggest the need to avoid concomitant use with strong and moderate inhibitors or inducers of CYP3A during the venetoclax ramp-up phase in chronic lymphocytic leukaemia (CLL) patients. For patients who have completed the ramp-up phase, a modification in venetoclax dose for use with strong and moderate inhibitors or inducers of CYP3A is recommended.
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Effects of CYP3A4 Inhibitors Ketoconazole and Verapamil and the CYP3A4 Inducer Rifampicin on the Pharmacokinetic Parameters of Fostamatinib: Results from In Vitro and Phase I Clinical Studies.
Martin, P, Gillen, M, Millson, D, Oliver, S, Brealey, C, Grossbard, EB, Baluom, M, Lau, D, Sweeny, D, Mant, T, et al
Drugs in R&D. 2016;(1):81-92
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Abstract
BACKGROUND Fostamatinib (R788) is a spleen tyrosine kinase (SYK) inhibitor. The active metabolite of fostamatinib, R406, is primarily metabolized by CYP3A4. OBJECTIVES The aim of this study was to characterize hepatic microsomal metabolism of R406 and confirm the role of CYP3A4 in R406 metabolism, determining whether co-administration of CYP3A4 inhibitors (ketoconazole, verapamil) or inducers (rifampicin) affects R406 pharmacokinetics. METHODS R406 stability was determined using human hepatic microsomes. The CYP450 isoforms responsible for R406 metabolism in humans were identified using expressed CYP450 isoforms and specific chemical inhibitors. The ketoconazole interaction study (double-blind, randomized, placebo-controlled, two-period crossover) involved fostamatinib administration (single 80-mg dose), alone and with ketoconazole (200 mg twice daily). The verapamil and rifampicin interaction studies (open-label, two-period, fixed-sequence) involved fostamatinib administration (single 150-mg dose), alone and with immediate-release verapamil (80 mg three times daily) or rifampicin (600 mg once daily). Standard pharmacokinetic parameters were calculated in all studies. RESULTS/DISCUSSION Hepatic microsomes showed time-dependent loss of R406 and formation of para-O-demethylated R406. Microsomal metabolism of R406 was markedly inhibited by CYP3A4 inhibitors and, in the expressed CYP450 studies, the rate of R406 disappearance was greatest with CYP3A4. In the clinical studies, co-administration of ketoconazole caused a 2-fold (CI 1.77-2.30) increase in R406 exposure. Verapamil increased R406 exposure (39% increase, CI 8-80), whereas rifampicin co-administration decreased exposure by 75% (CI 68-81). Fostamatinib was well tolerated. CONCLUSION The oxidative metabolism of R406 is predominantly catalyzed by CYP3A4. In clinical studies, exposure to R406 is affected by concomitant administration of CYP3A4 inducers/inhibitors. These findings should be taken into account when considering co-prescription of fostamatinib with such agents.
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Effects of Cytochrome P450 3A4 Inhibitors-Ketoconazole and Erythromycin-on Bitopertin Pharmacokinetics and Comparison with Physiologically Based Modelling Predictions.
Boetsch, C, Parrott, N, Fowler, S, Poirier, A, Hainzl, D, Banken, L, Martin-Facklam, M, Hofmann, C
Clinical pharmacokinetics. 2016;(2):237-47
Abstract
OBJECTIVE To assess the effect of strong and moderate cytochrome P450 (CYP) 3A4 inhibition on exposure of bitopertin, a glycine reuptake inhibitor primarily metabolized by CYP3A4, and to compare the results with predictions based on physiologically based pharmacokinetic (PBPK) modelling. METHODS The effects of ketoconazole and erythromycin were assessed in two male volunteer studies with open-label, two-period, fixed-sequence designs. Twelve subjects were enrolled in each of the studies. In period 1, a single dose of bitopertin was administered; in period 2, 400 mg ketoconazole was administered once daily for 17 days or 500 mg erythromycin was administered twice daily for 21 days. A single dose of bitopertin was coadministered on day 5. Pharmacokinetic parameters were derived by non-compartmental methods. Simulated bitopertin profiles using dynamic PBPK modelling for a typical healthy volunteer in GastroPlus(®) were used to predict changes in pharmacokinetic parameters. RESULTS In healthy volunteers, coadministration of ketoconazole increased the bitopertin area under the plasma concentration-time curve (AUC) from 0 to 312 h (AUC0-312h) 4.2-fold (90 % confidence interval [CI] 3.5-5.0) and erythromycin increased the AUC from time zero to infinity (AUC0-inf) 2.1-fold (90 % CI 1.9-2.3). The peak concentration (C max) increased by <25 % in both studies. Simulated bitopertin profiles using PBPK modelling showed good agreement with the observed AUC ratios in both studies. The predicted AUC0-inf ratios for the interaction with ketoconazole and erythromycin were 7.7 and 1.9, respectively. CONCLUSION Strong CYP3A4 inhibitors increase AUC0-inf of bitopertin 7- to 8-fold and hence should not be administered concomitantly with bitopertin. Moderate CYP3A4 inhibitors double AUC0-inf.
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An adaptive design to investigate the effect of ketoconazole on pharmacokinetics of GSK239512 in healthy male volunteers.
Xu, J, Hilpert, J, Wu, K, van Hecke, B, Collins, G, Patel, A, Mohindra, R, Davies, MJ, Xu, Y, Thompson, P
Journal of clinical pharmacology. 2015;(5):505-11
Abstract
This open label drug-drug interaction (DDI) study investigated the effect of a strong CYP3A inhibitor ketoconazole on the PK and safety profile of GSK239512. To mitigate the tolerability concerns of high GSK239512 exposures resulting from CYP3A inhibition, a 2-cohort adaptive design was used to facilitate a stepwise selection of dose levels and subject numbers. In Cohort 1, 6 subjects received a single dose of 20 μg GSK239512 alone and then 10 μg GSK239512 in combination with repeated once daily doses of 400 mg ketoconazole. The results from Cohort 1 demonstrated an approximately 1.5-fold increase in GSK239512 exposure with a good tolerability profile. This led to the adoption of a 3-session option in Cohort 2, in which 16 subjects received sequential single doses of 20 μg GSK239512 alone, 40 μg GSK239512 alone, and a single dose of 40 μg GSK239512 in combination with repeated once daily doses of 400 mg ketoconazole. The 2-cohort adaptive design proved effective in mitigating any potentially significant DDI risk to healthy subjects. Final results showed a 1.3-fold increase in GSK239512 exposure with ketoconazole, suggesting that in vivo metabolism of GSK239512 by CYP3A is unlikely to be the primary route of GSK239512 elimination.
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Effect of axitinib on the QT interval in healthy volunteers.
Ruiz-Garcia, A, Houk, BE, Pithavala, YK, Toh, M, Sarapa, N, Tortorici, MA
Cancer chemotherapy and pharmacology. 2015;(3):619-28
Abstract
PURPOSE Axitinib is a potent and selective inhibitor of vascular endothelial growth factor receptors 1-3, approved for second-line treatment of advanced renal cell carcinoma (RCC). Preclinical studies did not indicate potential for axitinib-induced delayed cardiac repolarization. METHODS The effect of axitinib on corrected QT (QTc) prolongation was evaluated with one-stage concentration-QTc response modeling using data from a definitive randomized crossover QT phase I study in healthy volunteers administered one single 5-mg axitinib dose alone or in the presence of steady-state ketoconazole (400 mg once daily). RESULTS Axitinib and ketoconazole had opposite effects on heart rate: Axitinib lowered it, ketoconazole raised it. The final analysis showed a flat relationship between QTc and axitinib concentration (slope -0.0314 ms·mL/ng) for axitinib alone. Mean highest placebo-matched change from baseline in QTc was -3.0 [90 % confidence interval (CI) -5.4, -0.6] ms. At supratherapeutic axitinib exposures achieved with potent cytochrome P450 3A4/5 inhibition by ketoconazole, the model predicted mean QTc change of 6.5 (90 % CI 4.4-8.5) ms. The slope population mean estimate was -0.331 (95 % CI -0.860, 0.198) ms·mL/µg for ketoconazole alone and 0.0725 (0.0445-0.1005) ms·mL/ng for axitinib in the presence of ketoconazole. The results were then compared with those obtained based on more widely used Fridericia's, Bazett's, and study-specific correction methods. CONCLUSIONS Since axitinib plasma concentrations observed in this study exceeded the range of concentrations observed in patients with RCC at the highest approved clinical dose (10 mg twice daily), axitinib was not associated with clinically significant QTc prolongation in target populations.
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The effects of ketoconazole and rifampin on the single-dose pharmacokinetics of crizotinib in healthy subjects.
Xu, H, O'Gorman, M, Tan, W, Brega, N, Bello, A
European journal of clinical pharmacology. 2015;(12):1441-9
Abstract
PURPOSE To investigate the potential effects of strong CYP3A inhibitor ketoconazole and strong CYP3A inducer rifampin on the pharmacokinetics of crizotinib in human. METHODS Two separate open-label, 2-period, 2-treatment, 1-sequence, crossover, single-dose studies were conducted in healthy subjects with and without ketoconazole or rifampin. Series of plasma samples were collected after each crizotinib dose to determine concentration of crizotinib and its metabolite PF-06260182. Relevant pharmacokinetic (PK) parameters for crizotinib and PF096269182 were estimated by standard non-compartmental analysis (NCA) method. RESULTS Co-administration of a single 150-mg oral dose of crizotinib with the strong CYP3A inhibitor ketoconazole resulted in an area under the plasma-concentration curve extrapolated to infinity (AUC0-inf) 3.2-fold that for crizotinib alone. Co-administration of a single 250-mg crizotinib dose with the strong CYP3A inducer rifampin caused an 82 % decrease in crizotinib AUC0-inf. Respective increases and decreases in systemic exposure to the crizotinib metabolite PF-06260182 following co-administration of ketoconazole and rifampin were greater than those seen for crizotinib. CONCLUSIONS These findings suggest that CYP3A plays an important role in the metabolism of both crizotinib and PF-06260182, with the extent of this role being greater for PF-06260182. There were no serious adverse events or deaths and no dose reductions or temporary or permanent discontinuations due to drug-related adverse events in either study.
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Two-way interaction study between ritonavir boosted danoprevir, a potent HCV protease inhibitor, and ketoconazole in healthy subjects.
Morcos, PN, Chang, L, Navarro, M, Chung, D, Smith, PF, Brennan, BJ, Tran, JQ
International journal of clinical pharmacology and therapeutics. 2014;(2):103-11
Abstract
BACKGROUND Danoprevir is a potent, highly selective, macrocyclic, orally bioavailable inhibitor of the hepatitis C virus protease, and a substrate of cytochrome P450 (CYP) 3A. It is co-administered with low-dose ritonavir, a potent CYP3A inhibitor, to enhance danoprevir pharmacokinetics. Ketoconazole is a substrate for and potent selective inhibitor of CYP3A. METHODS In this open-label, 3-period study, the 2-way interaction potential between ritonavir-boosted danoprevir (danoprevir/r) and ketoconazole was investigated in 18 healthy subjects. Subjects initially received ketoconazole 200 mg q24h for 4 days (Period 1) followed by a 7-day washout period. Danoprevir/r 100/100 mg q12h was then given for 10 days (Period 2) followed by a further 4 days of danoprevir/r 100/100 mg q12h plus ketoconazole 200 mg q24h (Period 3). Serial blood samples were collected for the determination of danoprevir, ritonavir and/or ketoconazole plasma concentrations, and calculation of pharmacokinetic parameters. Safety and tolerability were monitored throughout the study. RESULTS Co-administration of ketoconazole with danoprevir/r modestly increased the danoprevir AUCτ by 1.44-fold, with no effect on danoprevir Cmax. Co-administration of danoprevir/r with ketoconazole substantially increased ketoconazole AUCτ and Cmax by 3.71-fold and 1.73-fold, respectively. Danoprevir/r was well tolerated when administered alone or with ketoconazole. CONCLUSIONS These results indicate that the effect of potent CYP3A inhibitors, such as ketoconazole, on danoprevir/r pharmacokinetics is not likely to be clinically relevant.
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Evaluation of the effect of food and ketoconazole on the pharmacokinetics of the smoothened inhibitor PF-04449913 in healthy volunteers.
Shaik, MN, LaBadie, RR, Rudin, D, Levin, WJ
Cancer chemotherapy and pharmacology. 2014;(2):411-8
Abstract
PURPOSE To evaluate the effect of a potent cytochrome P450 3A4 (CYP3A4) inhibitor, ketoconazole, and separately the effect of food on PF-04449913 pharmacokinetics in healthy volunteers. METHODS This was an open-label, two-sequence, three-period, three-treatment, single-dose, crossover study. Subjects were randomized to receive single doses of 200 mg PF-04449913 after an overnight fast or after consuming a high-fat meal during Period 1 or 2, with a washout period of at least 8 days. In Period 3, all subjects received ketoconazole (400 mg/day) (days 1-7) and a co-administered single 200-mg PF-04449913 dose (day 4). RESULTS Geometric mean ratio of PF-04449913 in the presence of ketoconazole versus PF-04449913 alone was 2.40 [90% confidence interval (CI) 2.15, 2.68] for area under the plasma concentration-time curve from time zero to infinity (AUC(0-inf)) and 1.40 (90% CI 1.24, 1.58) for peak plasma concentration (C max). The geometric mean ratio for fed state compared with fasted state for AUC(0-inf) was 0.87 (90% CI 0.78, 0.97) and for C max was 0.66 (90% CI 0.56, 0.78). PF-04449913 was well tolerated, and all adverse events were mild to moderate. CONCLUSIONS PF-04449913 plasma exposures and peak concentrations were increased following concurrent administration of ketoconazole in healthy volunteers. These findings provide the upper limit for expected PF-04449913 exposures after co-administration of a strong CYP3A4 inhibitor in patients with cancer who routinely receive antifungal azoles. While a high-fat meal decreased PF-04449913 exposure, the differences in plasma exposure under the two conditions were not considered clinically meaningful.
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Effects of cytochrome P450 inhibitors and inducers on the metabolism and pharmacokinetics of ospemifene.
Lehtinen, T, Tolonen, A, Turpeinen, M, Uusitalo, J, Vuorinen, J, Lammintausta, R, Pelkonen, O, Scheinin, M
Biopharmaceutics & drug disposition. 2013;(7):387-95
Abstract
PURPOSE The objectives were to determine the cytochrome P450 (CYP) enzymes involved in the metabolism of ospemifene and its main hydroxylated metabolites and to examine the effects of CYP inhibitors and inducers on ospemifene pharmacokinetics. METHODS In vitro metabolism studies were conducted using human liver microsomes; CYP-selective inhibitors and CYP-specific substrates were used to determine the roles of nine CYP isoforms in ospemifene metabolism. Two Phase 1 clinical trials were conducted in healthy postmenopausal women; crossover designs examined the effects of pretreatment with the CYP modulators rifampicin, ketoconazole, fluconazole and omeprazole on ospemifene pharmacokinetics. RESULTS Although several CYP inhibitors decreased the in vitro formation of ospemifene metabolites, none of them completely blocked metabolism. Roles for CYP3A4, CYP2C9, CYP2C19 and CYP2B6 in the metabolism of ospemifene and its two main metabolites, 4--hydroxyospemifene and 4'-hydroxyospemifene, were confirmed. The in vivo experiments demonstrated that ospemifene serum concentrations were decreased by rifampicin pretreatment, increased by ketoconazole or fluconazole pretreatment, and minimally affected by omeprazole pretreatment. CONCLUSIONS The clinical pharmacokinetic findings and in vitro data suggest that CYP3A4 is important for ospemifene metabolism, but other CYP isoforms and metabolic pathways also contribute. Strong CYP3A or CYP2C9 inducers (e.g. rifampicin) would be expected to decrease the exposure to ospemifene. Ospemifene should be used with caution when coadministered with the modest CYP3A inhibitor ketoconazole and should not be coadministered with the potent CYP3A/CYP2C9/CYP2C19 inhibitor fluconazole. The potent CYP2C19 inhibitor omeprazole is unlikely to cause clinically significant changes in ospemifene pharmacokinetics.