Background: Calcium channel blockers (CCB) such as AML are the preferred first line antihypertensives in young (<55 years) black patients and older patients of all ethnicities. Due to CYP3A metabolism, interactions between CCB and antiretroviral therapy (ARV) are anticipated. For example, interactions between PI/r and CCB may lead to CCB overdose resulting in serious toxicity. It is therefore necessary to identify ARVs which are safe when patients are taking concomitant CCB. We aimed at investigating the PK of RAL and AML when co-administered. Methods: This Phase I, open-label, three period, cross-over, PK study enrolled healthy males and females, who following consent and screening procedures were randomized to receive RAL 400mg BID, RAL plus AML 5mg OD, and AML, or the same treatment in the opposite order. All phases lasted 7 days and PK sampling was performed at the end of each phase (Days 7, 14 and 21). RAL and AML concentrations were analysed by validated LC-MS/MS and PK parameters determined by non-compartmental methods (WinNonLin). Results: Seventeen (13 female) subjects completed the study and no serious adverse events were reported. Geometric mean ratios (GMR) and 90% confidence intervals (CI) of RAL (with AML versus alone) area under the curve (AUC0-12h), Cmax and Ctrough were 1.39 (0.87-2.29), 1.58 (0.84-3.09), and 0.78 (0.57-1.04). GMR and 90% CI of AML (with RAL versus alone) AUC0-24h, Cmax and Ctrough were 1.00 (0.89-1.12), 1.00 (0.90-1.12), and 0.93 (0.80-1.08). Coefficient of variation (CV) for RAL PK parameters with and without AML ranged between 69% and 98%. AML CV ranged between 27% and 42%. Conclusions: RAL did not alter AML plasma exposure and AML did not have a significant effect on RAL plasma concentrations, suggesting that coadministration of the two drugs is safe in the clinical setting.
Pharmacokinetics (PK) of the co-administration of raltegravir (RAL) and amlodipine (AML) to male and female healthy volunteers
D'AVOLIO, ANTONIO;BONORA, Stefano;DI PERRI, Giovanni;
2014-01-01
Abstract
Background: Calcium channel blockers (CCB) such as AML are the preferred first line antihypertensives in young (<55 years) black patients and older patients of all ethnicities. Due to CYP3A metabolism, interactions between CCB and antiretroviral therapy (ARV) are anticipated. For example, interactions between PI/r and CCB may lead to CCB overdose resulting in serious toxicity. It is therefore necessary to identify ARVs which are safe when patients are taking concomitant CCB. We aimed at investigating the PK of RAL and AML when co-administered. Methods: This Phase I, open-label, three period, cross-over, PK study enrolled healthy males and females, who following consent and screening procedures were randomized to receive RAL 400mg BID, RAL plus AML 5mg OD, and AML, or the same treatment in the opposite order. All phases lasted 7 days and PK sampling was performed at the end of each phase (Days 7, 14 and 21). RAL and AML concentrations were analysed by validated LC-MS/MS and PK parameters determined by non-compartmental methods (WinNonLin). Results: Seventeen (13 female) subjects completed the study and no serious adverse events were reported. Geometric mean ratios (GMR) and 90% confidence intervals (CI) of RAL (with AML versus alone) area under the curve (AUC0-12h), Cmax and Ctrough were 1.39 (0.87-2.29), 1.58 (0.84-3.09), and 0.78 (0.57-1.04). GMR and 90% CI of AML (with RAL versus alone) AUC0-24h, Cmax and Ctrough were 1.00 (0.89-1.12), 1.00 (0.90-1.12), and 0.93 (0.80-1.08). Coefficient of variation (CV) for RAL PK parameters with and without AML ranged between 69% and 98%. AML CV ranged between 27% and 42%. Conclusions: RAL did not alter AML plasma exposure and AML did not have a significant effect on RAL plasma concentrations, suggesting that coadministration of the two drugs is safe in the clinical setting.
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