Assessment of Pharmacokinetic Interactions Between Obeticholic Acid and Caffeine, Midazolam, Warfarin, Dextromethorphan, Omeprazole, Rosuvastatin, and Digoxin in Phase 1 Studies in Healthy Subjects

Edwards, Jeffrey E.; Eliot, Lise; Parkinson, Andrew; Karan, Sharon; MacConell, Leigh

doi:10.1007/s12325-017-0601-0

Cited by 21 publications

(21 citation statements)

References 22 publications

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“…Despite the numerous examples of CYP downregulation in vitro, there is no clear example of CYP in vitro downregulation translating into meaningful DDIs in the clinic. The possible exceptions are 1) the effect of obeticholic acid on caffeine but not its metabolite paraxanthine (Edwards et al, 2017) and 2) the simultaneous inhibition and downregulation of CYP2D6 mediated by bupropion (Sager et al, 2017). Notably, the European Medicines Agency has reviewed a clinical package for a drug that exhibited downregulation of CYP activity both in vitro and in vivo (Hariparsad et al, 2017); however, no details of this package are publicly available at this time.…”

Section: Discussionmentioning

confidence: 99%

Abemaciclib Does Not Have a Clinically Meaningful Effect on Pharmacokinetics of CYP1A2, CYP2C9, CYP2D6, and CYP3A4 Substrates in Patients with Cancer

et al. 2020

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Abemaciclib is an orally administered, potent inhibitor of cyclindependent kinases 4 and 6 and is metabolized extensively by CYP3A4. The effects of abemaciclib on several CYPs were qualified in vitro and subsequently evaluated in a clinical study. In vitro, human hepatocytes were treated with vehicle, abemaciclib, or abemaciclib metabolites [N-desethylabemaciclib (M2) or hydroxyabemaciclib (M20)]. mRNA levels for eight CYPs were measured using reversetranscription quantitative polymerase chain reaction, and, additionally, catalytic activities for three CYPs were determined. In the clinical study, adult patients with cancer received a drug cocktail containing CYP substrates [midazolam (3A), warfarin (2C9), dextromethorphan (2D6), and caffeine (1A2)] either alone or in combination with abemaciclib. Plasma pharmacokinetics (PK) samples were analyzed for all substrates, caffeine metabolite paraxanthine, and abemaciclib; polymorphisms of CYP2C9, CYP2D6, CYP3A4, and CYP3A5 were evaluated. In vitro, downregulation of CYP mRNA, including 1A2, 2B6, 2C8, 2C9, 2D6, and 3A, by abemaciclib and/or M2 and M20 was observed at clinically relevant concentrations. In humans, abemaciclib did not affect the PK of CYP2D6 or CYP2C9 substrates. Minor statistically significant but clinically irrelevant changes were observed for midazolam [area under the concentration versus time curve from zero to infinity (AUC 0-inf) (13% lower), C max (15% lower)], caffeine [AUC 0-inf (56% higher)], and paraxanthine: caffeine [area under the concentration versus time curve from 0 to 24 hours ratio (was approximately 30% lower)]. However, given the magnitude of the effect, these changes are not considered clinically relevant. In conclusion, the downregulation of CYP mRNA mediated by abemaciclib in vitro did not translate into clinically meaningful drug-drug interactions in patients with cancer. SIGNIFICANCE STATEMENT Despite observations that abemaciclib alters the mRNA of various CYP isoforms in vitro, a clinical study using a drug cocktail approach found no clinically meaningful drug-drug interactions between abemaciclib and a range of CYP substrates [midazolam (CYP3A4), S-warfarin (CYP2C9), dextromethorphan (CYP2D6), and caffeine (CYP1A2)]. This lack of translation suggests greater understanding of mechanisms of CYP downregulation is needed to accurately predict clinical drug-drug interaction risk from in vitro data.

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Section: Discussionmentioning

confidence: 99%

Abemaciclib Does Not Have a Clinically Meaningful Effect on Pharmacokinetics of CYP1A2, CYP2C9, CYP2D6, and CYP3A4 Substrates in Patients with Cancer

et al. 2020

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“…Although obeticholic acid was shown to inhibit CYP3A4 in vitro , a DDI study has demonstrated no clinically significant inhibition of CYP3A4 at the doses of obeticholic acid in clinical use. ( 52 ) Obeticholic acid is not expected to significantly inhibit or induce other cytochromes or drug transporters (Ocaliva product label).…”

Section: Investigational Agents For Nash and Potential Ddis In The Comentioning

confidence: 99%

New Drugs for NASH and HIV Infection: Great Expectations for a Great Need

et al. 2020

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on behalf of the SHIVER Network In recent years, there has been an increasing number of clinical trials for the treatment of nonalcoholic steatohepatitis (NASH). People living with human immunodeficiency virus (PLWH) are commonly excluded from these studies, usually due to concerns over drug-drug interactions associated with antiretroviral therapy. The Steatohepatitis in HIV Emerging Research Network, a group of international experts in hepatology and infectious diseases, discusses our current understanding on the interaction between human immunodeficiency virus and NASH, and the issues related to the inclusion of PLWH in NASH clinical trials. Recent trials addressing NASH treatment in PLWH are discussed. The risk of drug-drug interactions between antiretroviral therapy and aramchol, cenicriviroc, elafibranor, obeticholic acid and resmetirom (MGL-3196), which are currently in phase 3 trials for the treatment of NASH, are reviewed. A model for trial design to include PLWH is proposed, strongly advocating for the scientific community to include this group as a subpopulation within studies. (Hepatology 2020;71:1831-1844).

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“…Alternatively, we looked to a semisynthetic FXR agonist like obeticholic acid (6a-ethyl-chenodeoxycholic acid), which similarly elicits robust induction (.5-fold) of BSEP and small heterodimer partner mRNA expression in sandwich-cultured human hepatocytes (Zhang et al, 2017). But unlike chenodeoxycholic acid, clinical data are available for multidose obeticholic acid showing that it has a minimal effect on the AUC of an orally dosed BCRP or OATP probe drug (rosuvastatin) (Edwards et al, 2017). Consistent with such clinical data, Ijssennagger et al (2016) have reported that obeticholic acid (1 mM) elicits a relatively modest effect on OATP1B1 and OATP1B3 mRNA expression (vs. induction of ABCB11 mRNA) in precision-cut human liver slices.…”

Section: Studies With Fxr Agonistsmentioning

confidence: 99%

Induction of Human Intestinal and Hepatic Organic Anion Transporting Polypeptides: Where Is the Evidence for Its Relevance in Drug-Drug Interactions?

et al. 2019

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Organic anion transporting polypeptides (OATPs), expressed in human liver (OATP1B1, OATP1B3, and OATP2B1) and intestine (OATP2B1), govern the pharmacokinetics (PK) of drugs (e.g., statins) and endogenous substrates (e.g., coproporphyrin I [CPI]). Their expression is known to be modulated (e.g., disease, age, and environmental factors), and they also present as the loci of clinically relevant polymorphisms and drug interactions involving inhibition. In comparison, relatively few clinical reports describe the induction of OATPs, although the effect of inducers (e.g., rifampicin [RIF], carbamazepine [CBZ]) on OATP biomarker plasma levels and statin PK has been reported. Of note, available human tissue (e.g., biopsy) protein and messenger RNA expression profiling data indicate that OATPs in gut and liver are not induced by prototypical inducers such as RIF when compared with cytochrome P450 3A4 (CYP3A4), P-glycoprotein (Pgp), multidrug resistance-associated protein 2 (MRP2), and breast cancer resistance protein (BCRP). Such results are consistent with in vitro human hepatocyte data. Therefore, the observed impact of RIF, and possibly CBZ, on statin PK (>20% decrease in the area under the plasma concentration vs. time curve) cannot be ascribed to OATP induction with certainty. In fact, most statins and CPI have been shown to present variously as substrates of RIF-inducible proteins such as CYP3A4, Pgp, MRP2, and BCRP. Interpretation of multidose RIF data is further complicated by its autoinduction, which likely leads to decreased inhibition of OATP. In the absence of more conclusive OATP induction data, caution is needed when modeling drug-drug interactions involving multidose inducers such as RIF. SIGNIFICANCE STATEMENT Presently, there is limited direct clinical evidence supporting the notion that human liver and gut organic anion transporting polypeptides (OATPs) are inducible by agents like rifampicin (RIF). Such data need to be reconciled and will pose challenges for attempting to incorporate OATP induction into physiologically based pharmacokinetics models. Although disparate sets of tissue biopsy (atorvastatin and carbamazepine) and in vitro hepatocyte (phenobarbital, chenodeoxycholate, and amprenavir) data present OATP messenger RNA induction (‡2-fold) by agents beyond RIF, the clinical relevance of such data needs to be determined.

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Assessment of Pharmacokinetic Interactions Between Obeticholic Acid and Caffeine, Midazolam, Warfarin, Dextromethorphan, Omeprazole, Rosuvastatin, and Digoxin in Phase 1 Studies in Healthy Subjects

Cited by 21 publications

References 22 publications

Abemaciclib Does Not Have a Clinically Meaningful Effect on Pharmacokinetics of CYP1A2, CYP2C9, CYP2D6, and CYP3A4 Substrates in Patients with Cancer

Abemaciclib Does Not Have a Clinically Meaningful Effect on Pharmacokinetics of CYP1A2, CYP2C9, CYP2D6, and CYP3A4 Substrates in Patients with Cancer

New Drugs for NASH and HIV Infection: Great Expectations for a Great Need

Induction of Human Intestinal and Hepatic Organic Anion Transporting Polypeptides: Where Is the Evidence for Its Relevance in Drug-Drug Interactions?

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