Moderate Hepatic Impairment Does Not Affect Doravirine Pharmacokinetics

Khalilieh, Sauzanne; Yee, Ka Lai; Liu, Rachael; Li, Fan; Sánchez, Rosa I.; Auger, Patrice; Triantafyllou, Ilias; Stypinski, Daria; Lasseter, Kenneth C.; Marbury, Thomas; Iwamoto, Marian

doi:10.1002/jcph.857

Cited by 19 publications

(14 citation statements)

References 18 publications

(37 reference statements)

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“…The decrease in olaparib absorption could counteract the theoretical effect of decreased metabolism, resulting in little change in the net exposure to olaparib in patients with moderate hepatic impairment compared with those with normal hepatic function. In addition, it has also been reported that there is a lack of effect of moderate hepatic impairment on the PK of substrates that are largely cleared by CYP3A 25,26 . Taken together, the results of the current study and those previously reported suggest that mild or moderate hepatic impairment will have no clinically significant effect on exposure to olaparib.…”

Section: Discussionsupporting

confidence: 76%

Pharmacokinetics and safety of olaparib in patients with advanced solid tumours and mild or moderate hepatic impairment

Rolfo

Isambert

Italiano

et al. 2020

Brit J Clinical Pharma

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Aims Olaparib, a potent oral poly(ADP‐ribose) polymerase inhibitor, is partially hepatically cleared. We investigated the pharmacokinetics (PK) and safety of olaparib in patients with mild or moderate hepatic impairment to provide dosing recommendations. Methods This Phase I open‐label study assessed the PK, safety and tolerability of single doses of olaparib 300‐mg tablets in patients with advanced solid tumours. Patients had normal hepatic function (NHF), or mild (MiHI; Child–Pugh class A) or moderate (MoHI; Child–Pugh class B) hepatic impairment. Blood was collected for PK assessments for 96 hours. Patients could continue taking olaparib 300 mg twice daily for long‐term safety assessment. Results Thirty‐one patients received ≥1 dose of olaparib and 30 were included in the PK assessment. Patients with MiHI had an area under the curve geometric least‐squares mean (GLSmean) ratio of 1.15 (90% confidence interval 0.72, 1.83) and a GLSmean maximum plasma concentration ratio of 1.13 (0.82, 1.56) vs those with NHF. In patients with MoHI, GLSmean ratio for area under the curve was 1.08 (0.66, 1.74) and for maximum plasma concentration was 0.87 (0.63, 1.22) vs those with NHF. For patients with mild or moderate hepatic impairment, no new safety signals were detected. Conclusion Patients with MiHI or MoHI had no clinically significant changes in exposure to olaparib compared with patients with NHF. The safety profile of olaparib did not differ from a clinically relevant extent between cohorts. No olaparib tablet or capsule dose reductions are required for patients with MiHI or MoHI.

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Section: Discussionsupporting

confidence: 76%

Pharmacokinetics and safety of olaparib in patients with advanced solid tumours and mild or moderate hepatic impairment

Rolfo

Isambert

Italiano

et al. 2020

Brit J Clinical Pharma

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“…Steady-state AUC was selected as the exposure measure from which to judge clinical relevance from a safety perspective, as this parameter is an integration of concentrations over the 24-h dosing interval in which individuals are exposed to doravirine at steady state. In phase I trials, there was no evidence that the incidence of overall AEs or specific AEs was temporally associated with doravirine T max [11,15,[20][21][22][23][24][25][26][27][28][29][30][31], therefore suggesting that C max does not play a major role in safety or tolerability. In the phase IIb trial, there was no evidence of exposure-or dose-related toxicities across the range of 25-200 mg doses evaluated, and no meaningful association between doravirine steady-state exposure and the incidence of neuropsychiatric AEs or fasting lipid levels that would further limit the exposure of doravirine from a safety perspective [17].…”

Section: Definition Of the Bounds Of Clinical Relevancementioning

confidence: 98%

“…The effects of demographic factors including age, gender, hepatic impairment, and renal impairment on doravirine pharmacokinetics were evaluated in dedicated phase I trials in participants without HIV-1 infection [22,24,25]. In addition, a population pharmacokinetic analysis of individuals with (n = 959) and without (n = 341) HIV-1 infection was conducted across the phase I, II, and III trials to evaluate the effects of these factors-as well as body weight, body mass index (BMI), race, or ethnicity-on doravirine pharmacokinetics [14].…”

Section: Effect Of Demographic Factorsmentioning

confidence: 99%

“…Therefore, hepatic impairment can reasonably be expected to affect a sizeable proportion of people living with HIV; for those receiving antiretroviral therapy, this impairment may alter the pharmacokinetics of CYP3A-metabolized antiretroviral drugs [40]. A trial of doravirine in participants without HIV infection showed similar doravirine pharmacokinetics in the presence or absence of moderate hepatic impairment, and indicated that moderate hepatic impairment had no clinically meaningful effect on doravirine pharmacokinetics ( [25]. Doravirine was not studied in individuals with severe hepatic impairment [8,9].…”

Section: Hepatic Impairmentmentioning

confidence: 99%

“…A trial of doravirine in participants without HIV infection showed similar doravirine pharmacokinetics in the presence or absence of moderate hepatic impairment, and indicated that moderate hepatic impairment had no clinically meaningful effect on doravirine pharmacokinetics (Table 1 , Fig. 2 ) and that dose adjustment is not required for individuals with moderate or mild hepatic impairment [ 25 ]. Doravirine was not studied in individuals with severe hepatic impairment [ 8 , 9 ].…”

Section: Pharmacokinetics In Special Populationsmentioning

confidence: 99%

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Clinical Pharmacokinetics of the Novel HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitor Doravirine: An Assessment of the Effect of Patient Characteristics and Drug–Drug Interactions

et al. 2020

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Doravirine (MK-1439) is a novel non-nucleoside reverse transcriptase inhibitor indicated for the combination treatment of human immunodeficiency virus type-1 (HIV-1) infection. The recommended dose is 100 mg once daily. This review summarizes the pharmacokinetics of doravirine, the influence of intrinsic factors, and its drug-drug interaction (DDI) profile. Following oral administration, doravirine is rapidly absorbed (median time to maximum plasma concentration, 1-4 h) and undergoes cytochrome P450 (CYP)3A-mediated oxidative metabolism. Steady-state geometric means for AUC 0-24 , C 24 , and C max in individuals with HIV-1 following administration of doravirine 100 mg once daily are 37.8 μM•h, 930 nM, and 2260 nM, respectively. Age, gender, severe renal impairment, and moderate hepatic impairment have no clinically meaningful effect on doravirine pharmacokinetics, and there is limited potential for DDIs. No dose adjustment is necessary when doravirine is co-administered with strong CYP3A inhibitors. However, doravirine is contraindicated with strong CYP3A inducers (e.g., rifampin), and dose adjustment of doravirine is recommended for co-administration with the moderate CYP3A inducer, rifabutin. Included in this review are clinical trial data from phase I pharmacokinetic trials, including DDI trials and trials in participants with renal and hepatic disease but without HIV-1 infection (N = 326), as well as phase I, II, and III safety and efficacy trials in participants living with HIV-1 (N = 991). Based on these data, the pharmacokinetic profile of doravirine supports its use in diverse populations living with HIV-1 and allows co-administration with various antiretroviral agents and treatments for commonly occurring co-morbidities.

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Clinical Pharmacokinetics and Drug Interactions of Doravirine

Wilby

Eissa

2018

Eur J Drug Metab Pharmacokinet

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Doravirine is a new HIV-1 non-nucleoside reverse transcriptase inhibitor that has demonstrated a good efficacy and safety profile in clinical trials. It has a therapeutic profile that makes it an attractive option for treatment of HIV-1 infection. As such, there has been an increase in the published literature regarding the pharmacokinetics of doravirine and potential for drug-drug interactions. This review aimed to identify pharmacokinetic literature pertaining to doravirine, used findings from the literature to summarize its pharmacokinetic profile, and finally evaluated literature describing actual and potential drug interactions. Review findings show doravirine is well-absorbed, exhibits moderate protein binding activity, and is extensively metabolized by cytochrome P450 enzymes (specifically CYP3A). It has an elimination half-life of 12-21 h. Gender, age, moderate hepatic impairment, and co-administration with food did not greatly alter doravirine's pharmacokinetic profile. Drug interaction studies have shown doravirine does not affect the pharmacokinetics of dolutegravir or atorvastatin but may have its pharmacokinetics altered by rifampicin (rifampin) and other rifamycins (CYP3A inducers) and ritonavir (CYP3A inhibitor). No clinically significant interactions were noted between doravirine and an antacid (aluminum-magnesium), pantoprazole, ledipasvir/sofosbuvir, or elbasvir/grazoprevir. Further study is needed to better understand doravirine's efficacy and safety profile when co-administered with other agents known to be CYP inducers or inhibitors.

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Moderate Hepatic Impairment Does Not Affect Doravirine Pharmacokinetics

Cited by 19 publications

References 18 publications

Pharmacokinetics and safety of olaparib in patients with advanced solid tumours and mild or moderate hepatic impairment

Pharmacokinetics and safety of olaparib in patients with advanced solid tumours and mild or moderate hepatic impairment

Clinical Pharmacokinetics of the Novel HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitor Doravirine: An Assessment of the Effect of Patient Characteristics and Drug–Drug Interactions

Clinical Pharmacokinetics and Drug Interactions of Doravirine

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