Renal impairment (RI) is known to influence the pharmacokinetics of nonrenally eliminated drugs, although the mechanism and clinical impact is poorly understood. We assessed the impact of RI and single dose oral rifampin (RIF) on the pharmacokinetics of CYP3A, OATP1B, P‐gp, and BCRP substrates using a microdose cocktail and OATP1B endogenous biomarkers. RI alone had no impact on midazolam (MDZ), maximum plasma concentration (Cmax), and area under the curve (AUC), but a progressive increase in AUC with RI severity for dabigatran (DABI), and up to ~2‐fold higher AUC for pitavastatin (PTV), rosuvastatin (RSV), and atorvastatin (ATV) for all degrees of RI was observed. RIF did not impact MDZ, had a progressively smaller DABI drug‐drug interaction (DDI) with increasing RI severity, a similar 3.1‐fold to 4.4‐fold increase in PTV and RSV AUC in healthy volunteers and patients with RI, and a diminishing DDI with RI severity from 6.1‐fold to 4.7‐fold for ATV. Endogenous biomarkers of OATP1B (bilirubin, coproporphyrin I/III, and sulfated bile salts) were generally not impacted by RI, and RIF effects on these biomarkers in RI were comparable or larger than those in healthy volunteers. The lack of a trend with RI severity of PTV and several OATP1B biomarkers, suggests that mechanisms beyond RI directly impacting OATP1B activity could also be considered. The DABI, RSV, and ATV data suggest an impact of RI on intestinal P‐gp, and potentially BCRP activity. Therefore, DDI data from healthy volunteers may represent a worst‐case scenario for clinically derisking P‐gp and BCRP substrates in the setting of RI.

Although the primary hypothesis was not met, there were no clinically meaningful differences in PD, PK, or PK/PD parameters between older men and postmenopausal women, supporting further research on odanacatib (50 mg once weekly) as a treatment for male osteoporosis. Odanacatib was generally well tolerated.

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AimsMK‐1293 is an insulin glargine that has an amino acid sequence identical to that of Lantus, the originator insulin glargine. Two euglycaemic clamp studies, 1 in subjects with type 1 diabetes (T1D) and 1 in healthy subjects, were conducted to demonstrate pharmacokinetic (PK) and pharmacodynamic (PD) similarity between MK‐1293 and Lantus commercially procured in both the European Union (EU‐Lantus) and the USA (US‐Lantus).Materials and MethodsBoth studies were single‐dose, randomized, double‐blind, single‐centre, crossover studies with ≥7 days between dosing periods. A 2‐treatment, 4‐period replicate crossover study in T1D subjects (N = 76) compared the PK and PD of MK‐1293 to EU‐Lantus for 30 hours after dosing. A 3‐period crossover study in healthy subjects (N = 109) compared the PK and PD of MK‐1293, EU‐Lantus and US‐Lantus for 24 hours after dosing. In both studies, all subjects received single 0.4 units/kg subcutaneous doses of MK‐1293 or Lantus in all dosing periods. Pharmacokinetic assessment was based on LC‐MS/MS‐based measurement of the major insulin glargine metabolite (M1) and PD was characterized using the euglycaemic clamp platform.ResultsIn both studies, pre‐specified similarity criteria were met between MK‐1293 and Lantus for comparison of PK (AUC0‐24 and Cmax of M1) and PD (GIR‐AUC0‐24, GIR‐AUC0‐12, GIR‐AUC12‐24, and GIRmax) primary endpoints. All treatments were well tolerated.ConclusionBased on comparative assessment in both T1D and healthy subjects, it can be concluded that the PK and PD properties of MK‐1293 are highly similar to those of Lantus. (ClinicalTrials.gov: NCT02059174).

Rifampin has acute inhibitory and chronic inductive effects that can cause complex drug–drug interactions. Rifampin inhibits transporters including organic‐anion‐transporting polypeptide (OATP)1B and P‐glycoprotein (P‐gp), and induces enzymes and transporters including cytochrome P450 3A, UDP‐glucuronosyltransferase (UGT)1A, and P‐gp. This study aimed to separate inhibitory and inductive effects of rifampin on letermovir disposition and elimination (indicated for cytomegalovirus prophylaxis in hematopoietic stem cell transplant recipients). Letermovir is a substrate of UGT1A1/3, P‐gp, and OATP1B, with its clearance primarily mediated by OATP1B. Letermovir (single‐dose) administered with rifampin (single‐dose) resulted in increased letermovir exposure through transporter inhibition. Chronic coadministration with rifampin (inhibition plus potential OATP1B induction) resulted in modestly decreased letermovir exposure vs. letermovir alone. Letermovir administered 24 hours after the last rifampin dose (potential OATP1B induction) resulted in markedly decreased letermovir exposure. These data suggest rifampin may induce transporters that clear letermovir; the modestly reduced letermovir exposure with chronic rifampin coadministration likely reflects the net effect of inhibition and induction. OATP1B endogenous biomarkers coproporphyrin (CP) I and glycochenodeoxycholic acid‐sulfate (GCDCA‐S) were also analyzed; their exposures increased after single‐dose rifampin plus letermovir, consistent with OATP1B inhibition and prior reports of inhibition by rifampin alone. CP I and GCDCA‐S exposures were substantially reduced with letermovir administered 24 hours after the last dose of rifampin vs. letermovir plus chronic rifampin coadministration. This study suggests that OATP1B induction may contribute to reduced letermovir exposure after chronic rifampin administration, although given the complexity of letermovir disposition alternative mechanisms are not fully excluded.