Eltrombopag, an oral thrombopoietin receptor agonist, has no impact on the pharmacokinetic profile of probe drugs for cytochrome P450 isoenzymes CYP3A4, CYP1A2, CYP2C9 and CYP2C19 in healthy men: a cocktail analysis

Jenkins, Julian; Williams, Daphne; Deng, Yanli; Collins, David; Kitchen, V. S.

doi:10.1007/s00228-009-0716-6

Cited by 13 publications

(5 citation statements)

References 24 publications

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“…To detect any potential effects of DAC HYP on the activities of CYP isoenzymes, the probe drug cocktail was administered 7 days after the third dose of DAC HYP 150 mg SC every 4 weeks (the clinical dose investigated in phase 3 studies) based on the following PK and PD considerations: ~90% of steady‐state exposure would be achieved after three doses of DAC HYP based on the terminal half‐life of ~2–3 weeks; time to maximum concentration (C max ) following SC dosing of DAC HYP is ~7 days; and the increase of serum IL‐2 reached plateau after 4 weeks of DAC HYP dosing. The sample size for this study is similar to that commonly used in cocktail drug interaction studies ( n = 15–21) .…”

Section: Methodsmentioning

confidence: 99%

“…Urine samples for the measurement of dextromethorphan and dextrorphan were collected over the 12‐h period immediately after probe drug cocktail administration. The PK sampling schedules were deemed adequate because they have been used in other probe drug cocktail studies . Blood samples for the measurement of serum DAC HYP concentrations were collected pre‐dose in period 2.…”

Section: Methodsmentioning

confidence: 99%

“…A cocktail approach is an effective way to evaluate in vivo TP‐DIs in the target population because it involves administration of a mixture of specific probe substrates of multiple CYP enzymes and/or transporters in a single TP‐DI study to evaluate the effect of a therapeutic protein's inhibition or induction potential . A validated and commonly used modified ‘Cooperstown 5 + 1 cocktail’ consisting of oral midazolam (CYP3A), caffeine (CYP1A2), warfarin + vitamin K (CYP2C9), omeprazole (CYP2C19) and dextromethorphan (CYP2D6) has been shown to be safe and well tolerated in patients and healthy volunteers .…”

Section: Introductionmentioning

confidence: 99%

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Therapeutic protein–drug interaction assessment for daclizumab high‐yield process in patients with multiple sclerosis using a cocktail approach

Tran

Othman

Wolstencroft

et al. 2016

Brit J Clinical Pharma

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AIMSTo characterize the potential effect of daclizumab high-yield process (DAC HYP), a monoclonal antibody that blocks the highaffinity interleukin-2 receptors for treatment of multiple sclerosis, on activity of cytochrome P450 (CYP) enzymes. METHODSTwenty patients with multiple sclerosis received an oral cocktail of probe substrates of CYP1A2 (caffeine 200 mg), CYP2C9 (warfarin 10 mg/vitamin K 10 mg), CYP2C19 (omeprazole 40 mg), CYP2D6 (dextromethorphan 30 mg) and CYP3A (midazolam 5 mg) on two sequential occasions: 7 days before and 7 days after subcutaneous administration of DAC HYP 150 mg every 4 weeks for three doses. Serial pharmacokinetic blood samples up to 96 h post dose and 12-h urine samples were collected on both occasions. Area under the curve (AUC) for caffeine, S-warfarin, omeprazole and midazolam, and urine dextromethorphan to dextrorphan ratio were calculated. Statistical analyses were conducted on log-transformed parameters using a linear mixedeffects model. RESULTSThe 90% confidence intervals (CIs) for the geometric mean ratio (probe substrate with DAC HYP/probe substrate alone) for caffeine AUC from 0-12 h (0.93-1.15), S-warfarin AUC from 0 to infinity (AUC[0-inf]) (0.95-1.06), omeprazole AUC(0-inf) (0.88-1.13) and midazolam AUC(0-inf) (0.89-1.15) were within the no-effect boundary of 0.80-1.25. The geometric mean ratio for urine dextromethorphan to dextrorphan ratio was 1.01, with the 90% CI (0.76-1.34) extending slightly outside the no-effect boundary, likely due to high variability with urine collections and CYP2D6 activity. CONCLUSIONSDAC HYP treatment in patients with multiple sclerosis had no effect on CYP 1A2, 2C9, 2C19, 2D6 and 3A activity. British Journal of Clinical Pharmacology WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Therapeutic proteins that modulate cytokine activities can indirectly influence expression of cytochrome P450 (CYP) isoenzymes by affecting cytokine concentrations, and consequently may alter CYP-mediated metabolism of small molecule drugs when given in combination. Interleukin-2 (IL-2) and its modulators have been implicated in CYP-mediated drug interactions.• Daclizumab high-yield process (HYP) is a humanized monoclonal antibody that selectively blocks the alpha subunit (CD25) of the high-affinity IL-2 receptors and is being developed for treatment of multiple sclerosis.• Daclizumab HYP treatment increases systemic IL-2 levels. WHAT THIS STUDY ADDS• The study demonstrates that repeated administration of daclizumab HYP to patients with multiple sclerosis has no effect on the metabolic activity of the evaluated CYP enzymes.• Results provide important clinical information on impact of cytokine modulators on CYP activities, contributing to the clinical database to guide future recommendation on therapeutic protein-drug interaction assessment.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Therapeutic protein–drug interaction assessment for daclizumab high‐yield process in patients with multiple sclerosis using a cocktail approach

Tran

Othman

Wolstencroft

et al. 2016

Brit J Clinical Pharma

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“…Their probes have been widely used to evaluate the activities of the individual CYPs in the field of drug metabolism [6] . The cocktail approach involves the administration of multiple probes simultaneously and the measurement of the plasma kinetics of probes [7,8] , which is more convenient and saves costs and time compared with single-probe substrate studies [9][10][11][12] . In this study, a "cocktail" approach with the probes theophylline (CYP1A2), midazolam (CYP3A), chlorzoxazone (CYP2E1), dextromethorphan (CYP2D6), omeprazole (CYP2C19) and diclofenac (CYP2C9) [13,14] were used to investigate whether caderofloxacin affects the activity of its corresponding CYPs in rats.…”

Section: Introductionmentioning

confidence: 99%

Chronic administration of caderofloxacin, a new fluoroquinolone, increases hepatic CYP2E1 expression and activity in rats

et al. 2016

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Aim: Caderofloxacin is a new fluoroquinolone that is under phase III clinical trials in China. Here we examined the effects of caderofloxacin on rat hepatic cytochrome P450 (CYP450) isoforms as well as the potential of caderofloxacin interacting with co-administered drugs. Methods: Male rats were treated with caderofloxacin (9 mg/kg, ig) once or twice daily for 14 consecutive days. The effects of caderofloxacin on CYP3A, 2D6, 2C19, 1A2, 2E1 and 2C9 were evaluated using a "cocktail" of 6 probes (midazolam, dextromethorphan, omeprazole, theophylline, chlorzoxazone and diclofenac) injected on d 0 (prior to caderofloxacin exposure) and d 15 (after caderofloxacin exposure). Hepatic microsomes from the caderofloxacin-treated rats were used to assess CYP2E1 activity and chlorzoxazone metabolism. The expression of CYP2E1 mRNA and protein in hepatic microsomes was analyzed with RT-PCR and Western blotting, respectively. Results: Fourteen-day administration of caderofloxacin significantly increased the activity of hepatic CYP2E1, leading to enhanced metabolism of chlorzoxazone. In vitro microsomal study confirmed that CYP2E1 was a major metabolic enzyme involved in chlorzoxazone metabolism, and the 14-d administration of caderofloxacin significantly increased the activity of CYP2E1 in hepatic microsomes, resulting in increased formation of 6-hydroxychlorzoxazone. Furthermore, the 14-d administration of caderofloxacin significantly increased the expression of CYP2E1 mRNA and protein in liver microsomes, which was consistent with the pharmacokinetic results. Conclusion: Fourteen-day administration of caderofloxacin can induce the expression and activity of hepatic CYP2E1 in rats. When caderofloxacin is administered, a potential drug-drug interaction mediated by CYP2E1 induction should be considered.

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“…The coadministration of LPV/RTV with eltrombopag could alter plasma eltrombopag exposure through metabolic induction or ABCG2 (BCRP) inhibition. No impact of eltrombopag on plasma LPV or RTV concentrations was expected, as eltrombopag does not inhibit or induce CYP enzymes (15). Although eltrombopag inhibits SLCO1B1 (OATP1B1) and ABCG2 (BCRP) transporters and UGTs (3,13), these mechanisms of interaction were not predicted to alter plasma LPV/RTV exposure.…”

mentioning

confidence: 95%

Assessment of the Pharmacokinetic Interaction between Eltrombopag and Lopinavir-Ritonavir in Healthy Adult Subjects

Wire

McLean

Pendry

et al. 2012

Antimicrob Agents Chemother

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Eltrombopag is an orally bioavailable thrombopoietin receptor agonist that is approved for the treatment of chronic idiopathic thrombocytopenic purpura. It is being developed for other medical disorders that are associated with thrombocytopenia. Patients with human immunodeficiency virus (HIV) may suffer from thrombocytopenia as a result of their HIV disease or coinfection with hepatitis C virus (HCV). HIV medications, particularly ritonavir (RTV)-boosted HIV protease inhibitors, are involved in many drug interactions. This study evaluated the potential drug-drug interaction between eltrombopag and lopinavir (LPV)/ RTV. Forty healthy adult subjects enrolled in this open-label, three-period, single-sequence crossover study received a single 100-mg dose of eltrombopag (period 1), LPV/RTV at 400/100 mg twice daily (BID) for 14 days (period 2), and LPV/RTV at 400/ 100 mg BID (2 doses) with a single 100-mg dose of eltrombopag administered with the morning LPV/RTV dose (period 3). There was a 3-day washout between periods 1 and 2 and no washout between periods 2 and 3. Serial pharmacokinetic samples were collected during 72 h in periods 1 and 3 and during 12 h in period 2. The coadministration of 400/100 mg LPV/RTV BID with a single dose of 100 mg eltrombopag decreased the plasma eltrombopag area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC 0-ؕ ) by 17%, on average, with no change in plasma LPV/RTV exposure. Adverse events (AEs) reported in period 2 were consistent with known LPV/RTV AEs, such as diarrhea, abdominal pain, nausea, vomiting, rash, and fatigue. No subjects withdrew due to AEs, and no serious AEs were reported. These study results suggest that platelet counts should be monitored and the eltrombopag dose adjusted accordingly if LPV/RTV therapy is initiated or discontinued.

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Eltrombopag, an oral thrombopoietin receptor agonist, has no impact on the pharmacokinetic profile of probe drugs for cytochrome P450 isoenzymes CYP3A4, CYP1A2, CYP2C9 and CYP2C19 in healthy men: a cocktail analysis

Abstract: Once-daily administration of eltrombopag 75 mg for 7 days did not alter CYP3A4, CYP1A2, CYP2C9 or CYP2C19 activity in healthy volunteers.

Cited by 13 publications

References 24 publications

Therapeutic protein–drug interaction assessment for daclizumab high‐yield process in patients with multiple sclerosis using a cocktail approach

Therapeutic protein–drug interaction assessment for daclizumab high‐yield process in patients with multiple sclerosis using a cocktail approach

Chronic administration of caderofloxacin, a new fluoroquinolone, increases hepatic CYP2E1 expression and activity in rats

Assessment of the Pharmacokinetic Interaction between Eltrombopag and Lopinavir-Ritonavir in Healthy Adult Subjects

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