A Microdose Cocktail to Evaluate Drug Interactions in Patients with Renal Impairment

Abstract

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.

Quantification of CYP3A and Drug Transporters Activity in Healthy Young, Healthy Elderly and Chronic Kidney Disease Elderly Patients by a Microdose Cocktail Approach

“…Additionally, as MDZ is an intermediate hepatic extraction drug, a physiological reduction of hepatic blood flow anticipated in the elderly might also contribute to the observed reduction in hepatic clearance of MDZ (Dundee et al, 1986;Amrein and Hetzel, 1990). Our finding that CKD was not associated with changes in pharmacokinetic profiles of MDZ was consistent with a previous study where neither AUC nor C max of MDZ was affected by renal impairment (Tatosian et al, 2020).…”

“…The cocktail drugs include 1) midazolam (MDZ), a specific and selective substrate for CYP3A; 2) dabigatran etexilate (DABE), a selective substrate for intestinal P-gp; 3) pitavastatin (PTV), a relatively selective substrate for OATP1B; 4) rosuvastatin (RSV), a substrate of BCRP and OATP1B; and 5) atorvastatin (ATV), a substrate of CYP3A, OATP1B, BCRP, and P-gp. This cocktail was subsequently studied in patients with CKD, and the study results suggested that CKD reduces intestinal P-gp and BCRP activity (Tatosian et al, 2020). However, whether the observed changes were due solely to CKD or as a consequence of advancing age, remains inconclusive.…”

PBPK Model of Coproporphyrin I: Evaluation of the Impact of SLCO1B1 Genotype, Ethnicity, and Sex on its Inter‐Individual Variability

“…Simulated decreased AUCR in 521CC is consistent with data reported with clinical OATP1B probes 3,6 and suggests the risk of underestimation of the magnitude of transporter-mediated interaction if these subjects are included in a CPI-drug interaction study, which is more likely to happen in clinical studies performed without prior genotyping (e.g., first-in-human study) or in populations with higher prevalence of 521CC. 48 In contrast, any changes in CPI synthesis did not affect fraction transported via OATP1B and simulated AUCR, highlighting no risk of underestimation of the OATP1B interaction magnitude if female subjects are included in the study. As exemplified here, the modeling of CPI gives us prospective insights of clinical output and enables optimal clinical design to increase likelihood of success.…”

“…As exemplified here, the modeling of CPI gives us prospective insights of clinical output and enables optimal clinical design to increase likelihood of success. Furthermore, the physiological description of the liver processes in the CPI model enables the extension of the model to other special populations (e.g., evaluation of the changes in OATP1B activity in the chronic kidney disease population) 49,50 …”

“…Furthermore, the physiological description of the liver processes in the CPI model enables the extension of the model to other special populations (e.g., evaluation of the changes in OATP1B activity in the chronic kidney disease population). 49,50 In conclusion, this study evaluated the impact of the genotype of OATP1B1 c521T>C, ethnicity, and sex on CPI baseline and its OATP1B-mediated interaction potential. For the first time, this revised CPI population PBPK model implemented reduced active uptake due to OATP1B1 polymorphism, ethnic differences in active uptake between Asian-Indians and Caucasians, and reduced CPI synthesis in women.…”