Acute and Chronic Effects of Rifampin on Letermovir Suggest Transporter Inhibition and Induction Contribute to Letermovir Pharmacokinetics

Abstract

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.

Cluster Gauss‐Newton method analyses of PBPK model parameter combinations of coproporphyrin‐I based on OATP1B‐mediated rifampicin interaction studies

“…Among them, the heme synthesis by‐product, coproporphyrin I (CP‐I), 8 , 9 , 10 has been used as biomarkers for assessing OATP1B‐mediated DDIs. 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 CP‐I has advantages in the evaluation of OATP1B‐mediated DDIs, such as negligible effects of food and no circadian rhythm, 9 , 10 as well as its specificity and sensitivity for OATP1B inhibition. Consequently, the pharmaceutical industry is beginning to use CP‐I in combination with other OATP1B‐DDI biomarkers in setting exclusion criteria for drug candidates with high DDI risk, guiding decisions regarding the conduct of clinical DDI studies, and designing phase III trials with a minimum risk of DDI.…”

“…Various endogenous OATP1B substrates have been proposed as surrogate probes 5–7 to facilitate the risk assessment of pharmacokinetic DDIs in early clinical phases. Among them, the heme synthesis by‐product, coproporphyrin I (CP‐I), 8–10 has been used as biomarkers for assessing OATP1B‐mediated DDIs 11–18 . CP‐I has advantages in the evaluation of OATP1B‐mediated DDIs, such as negligible effects of food and no circadian rhythm, 9,10 as well as its specificity and sensitivity for OATP1B inhibition.…”

Pharmacokinetics, Safety, and Tolerability of Letermovir Following Single‐ and Multiple‐Dose Administration in Healthy Japanese Subjects

“…Rifampin was used as a probe inhibitor of OATP1B1/3 and P‐gp following acute dosing, and an inducer of UGT1A1 and P‐gp following chronic dosing 16–19 . Rifampin coadministration resulted in an initial increase in letermovir plasma concentrations (due to OATP1B1/3 inhibition) that was not clinically relevant, followed by clinically relevant decreases in letermovir plasma concentrations with continued rifampin coadministration 20 …”

“…[16][17][18][19] Rifampin coadministration resulted in an initial increase in letermovir plasma concentrations (due to OATP1B1/3 inhibition) that was not clinically relevant, followed by clinically relevant decreases in letermovir plasma concentrations with continued rifampin coadministration. 20 Letermovir was shown in vitro to be an inducer and time-dependent inhibitor of CYP3A4, 9 though in vivo results using a CYP3A probe substrate (midazolam) suggest that letermovir is a net moderate inhibitor of CYP3A. 21 Letermovir increases the plasma concentrations of the immunosuppressants CsA, tacrolimus, and sirolimus and may increase exposures to other sensitive CYP3A substrates when coadministered with letermovir.…”

Effects of rifampicin on porphyrin metabolism in healthy volunteers

“…Indeed, there is recent evidence that even after 14-day rifampicin dosing (i.e., fully induced state), rifampicin elevates plasma coproporphyrin I. 38 Thus, the mechanism of increased urine excretion of coproporphyrin I detected in our study is most likely hepatic OATP1B inhibition by rifampicin, but the role of induction of hepatic or kidney MRP2 cannot be excluded. It should be noted that as induction is a time-dependent phenomenon, our 7-day rifampicin dosing, although a typical duration in the field, might have been too short a time period for the effects of the induction to fully manifest.…”