CYP‐mediated drug–drug interactions with evacetrapib, an investigational CETP inhibitor: <i>in vitro</i> prediction and clinical outcome

Cannady, Ellen A.; Suico, Jeffrey G.; Wang, Ming Dauh; Friedrich, Stuart; Rehmel, Jessica; Nicholls, Stephen J.; Krueger, Kathryn A.

doi:10.1111/bcp.12730

Cited by 10 publications

(4 citation statements)

References 19 publications

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“…Carotegrast methyl inhibitory activity against CYP3A4 appeared to have reached almost steady state 7 days after repeated administration of carotegrast methyl, and evaluation on Day 14, as set in this study, seemed reasonable. The carotegrast methyl inhibitory activity disappeared 14 days after the end of administration, as was also reported for evacetrapib 33 …”

Section: Discussionsupporting

confidence: 79%

“…The carotegrast methyl inhibitory activity disappeared 14 days after the end of administration, as was also reported for evacetrapib. 33 Carotegrast methyl also affected the PK of atorvastatin, a moderate substrate drug susceptible to PK interactions due to inhibition of CYP3A4, [23][24][25] and increased atorvastatin exposure AUC 0-t by 1.8-fold on Day 7 and 2.1-fold on Day 14, compared to atorvastatin administration alone (Day À1). The C max of atorvastatin was slightly increased by coadministration with carotegrast methyl.…”

Section: Discussionmentioning

confidence: 99%

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Evaluation of the potential drug–drug interactions of carotegrast methyl with midazolam, prednisolone or atorvastatin in healthy adults

Matsuki,

Oikawa,

Koyama

et al. 2023

Brit J Clinical Pharma

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AimsThis study evaluated drug–drug interactions between the CYP3A4 inhibitor carotegrast methyl and the other CYP3A4 substrates, midazolam, atorvastatin and prednisolone.MethodsA total of 88 healthy volunteers orally received carotegrast methyl 960 mg 3 times daily for 14 days. A single oral (5 mg) or intravenous (0.017 mg kg−1) midazolam, oral (5 mg) prednisolone or oral (10 mg) atorvastatin was administered before, with and after carotegrast methyl treatment. When the 90% confidence interval (CI) for the geometric mean ratios of the pharmacokinetic (PK) parameters with coadministration with carotegrast methyl (Day 14) to those before carotegrast methyl administration was between 0.80 and 1.25, no PK interaction were deemed.ResultsThe Cmax and AUC0‐t of oral midazolam before administration of carotegrast methyl were 30.9 ± 9.8 ng mL−1 and 74.5 ± 21.9 ng h mL−1, respectively. The geometric mean ratio of the Cmax and AUC0‐t of midazolam on Day 14 to those on Day −1 was 1.86 (90% CI, 1.64–2.11) and 3.07 (90% CI, 2.81–3.35), which did not fall within the range of 0.80–1.25, suggesting that carotegrast methyl had a PK interaction with midazolam. Similar PK interactions were found for intravenous midazolam and atorvastatin, but not for prednisolone. The inhibitory effect of carotegrast methyl on CYP3A4‐mediated metabolism of midazolam and atorvastatin had almost disappeared by 14 days after the end of administration.ConclusionCarotegrast methyl was classified as a moderate CYP3A4 inhibitor in humans. Carotegrast methyl might enhance the action of drugs that are metabolized by CYP3A4.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Evaluation of the potential drug–drug interactions of carotegrast methyl with midazolam, prednisolone or atorvastatin in healthy adults

Matsuki,

Oikawa,

Koyama

et al. 2023

Brit J Clinical Pharma

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“…3). The CYP2C9-only model considerably underpredicted intravenous and oral clearance, when employing (Back et al, 1988;Tremaine et al, 1997;Cannady et al, 2015;Gillen et al, 2017). conc., concentration.…”

Section: Oat2-mediated Hepatic Uptake Of Tolbutamidementioning

confidence: 99%

Organic Anion Transporter 2 Mediates Hepatic Uptake of Tolbutamide, a CYP2C9 Probe Drug

Mathialagan

Tylaska

et al. 2018

J Pharmacol Exp Ther

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Tolbutamide is primarily metabolized by CYP2C9, and, thus, is frequently applied as a clinical probe substrate for CYP2C9 activity. However, there is a marked discrepancy in the in vitro-in vivo extrapolation of its metabolic clearance, implying a potential for additional clearance mechanisms. The goal of this study was to evaluate the role of hepatic uptake transport in the pharmacokinetics of tolbutamide and to identify the molecular mechanism thereof. Transport studies using singly transfected cells expressing six major hepatic uptake transporters showed that tolbutamide is a substrate to organic anion transporter 2 (OAT2) alone with transporter affinity [Michaelis-Menten constant ()] of 19.5 ± 4.3 M. Additionally, OAT2-specific transport was inhibited by ketoprofen (an OAT2 inhibitor) and 1 mM rifamycin SV (pan inhibitor), but not by cyclosporine and rifampicin (OAT polypeptides/Na-taurocholate cotransporting polypeptide inhibitors). Uptake studies in primary human hepatocytes confirmed the predominant role of OAT2 in the active uptake with significant inhibition by rifamycin SV and ketoprofen, but not by the other inhibitors. Concentration-dependent uptake was noted in human hepatocytes with active transport characterized by and values of 39.3 ± 6.6 M and 426 ± 30 pmol/min per milligram protein, respectively. Bottom-up physiologically based pharmacokinetic modeling was employed to verify the proposed role of OAT2-mediated hepatic uptake. In contrast to the rapid equilibrium (CYP2C9-only) model, the permeability-limited (OAT2-CYP2C9 interplay) model better described the plasma concentration-time profiles of tolbutamide. Additionally, the latter well described tolbutamide pharmacokinetics in carriers of genetic variants and quantitatively rationalized its known drug-drug interactions. Our results provide first-line evidence for the role of OAT2-mediated hepatic uptake in the pharmacokinetics of tolbutamide, and imply the need for additional clinical studies in this direction.

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“…The carotegrast methyl inhibitory activity disappeared 14 days after the end of administration as was also reported for evacetrapib. 30 Carotegrast methyl also affected the PK of atorvastatin, a moderate substrate drug susceptible to PK interactions due to inhibition of CYP3A4, [23][24][25] and increased atorvastatin exposure AUC 0-t by 1.8-fold on day 7 and 2.1-fold on day 14, compared to atorvastatin administration alone (day -1). Carotegrast methyl did not affect the PK of prednisolone, which is a drug commonly used to treat UC colitis and known to be metabolized by CYP3A4.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the potential drug-drug interactions of carotegrast methyl with midazolam, prednisolone, or atorvastatin in healthy adults

Matsuki,

Oikawa,

Koyama

et al. 2023

Preprint

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Aims: To evaluate drug-drug interactions between carotegrast methyl, a CYP3A4 inhibitor, and other CYP3A4 substrates, midazolam, atorvastatin, and prednisolone. Methods: A total of 88 healthy volunteers orally received carotegrast methyl 960 mg three times daily for 14 days. A single oral (5 mg) or intravenous (0.017 mg kg) midazolam, oral (5 mg) prednisolone, or oral (10 mg) atorvastatin was administered before, with, and after carotegrast methyl treatment. When the 90% confidence interval (CI) for the geometric mean ratios of the pharmacokinetic (PK) parameters with coadministration with carotegrast methyl (day 14) to those before carotegrast methyl administration was between 0.80 and 1.25, no PK interaction were deemed. Results: The C and AUC of oral midazolam before administration of carotegrast methyl was 30.9 ± 9.8 ng mL and 74.5 ± 21.9 ng h mL, respectively. The geometric mean ratio of the C and AUC of midazolam on day 14 to those on day -1 was 1.86 (90% CI, 1.64 – 2.11) and 3.07 (90% CI, 2.81 – 3.35), which did not fall within the range of 0.80 – 1.25, suggesting that carotegrast methyl had a PK interaction with midazolam. Similar PK interactions were found for intravenous midazolam and atorvastatin, but not for prednisolone. The inhibitory effect of carotegrast methyl on CYP3A4-mediated metabolism of midazolam and atorvastatin had almost disappeared by 14 days after the end of administration. Conclusion: Carotegrast methyl was classified as a moderate CYP3A4 inhibitor in humans. Carotegrast methyl might enhance the action of drugs that are metabolized by CYP3A4.

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CYP‐mediated drug–drug interactions with evacetrapib, an investigational CETP inhibitor: in vitro prediction and clinical outcome

Cited by 10 publications

References 19 publications

Evaluation of the potential drug–drug interactions of carotegrast methyl with midazolam, prednisolone or atorvastatin in healthy adults

Evaluation of the potential drug–drug interactions of carotegrast methyl with midazolam, prednisolone or atorvastatin in healthy adults

Organic Anion Transporter 2 Mediates Hepatic Uptake of Tolbutamide, a CYP2C9 Probe Drug

Evaluation of the potential drug-drug interactions of carotegrast methyl with midazolam, prednisolone, or atorvastatin in healthy adults

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