Changes in clearance, volume and bioavailability of immunosuppressants when given with HAART in HIV‐1 infected liver and kidney transplant recipients

Abstract

Solid organ transplantation in Human Immunodeficiency Virus 1 (HIV)-infected individuals requiring concomitant use of immunosuppressants (IS) [e.g., cyclosporine (CsA) or tacrolimus (TAC)] and antiretrovirals (ARVs) [e.g., protease inhibitors (PIs) and/or non-nucleoside reverse transcriptase inhibitors (NNRTIs)] is complicated by significant drug interactions. We describe the pharmacokinetics of CsA and TAC in 52 patients on both IS and NNRTIs, PIs, or combined NNRTIs+PIs, in studies conducted at 2 weeks, 3, 6, 12 and 24 months after transplantation. CsA and TAC blood concentrations were measured by LC/MS/MS. This multisubject, varied ARV-IS drug combination, longitudinal observational patient study provided a unique opportunity to examine the effect of different ARV drugs on IS PK by comparing ratios of parameters over time and between PK parameters. Subjects taking concomitant PIs exhibited increases in CsA and TAC exposure (AUC/dose) due to increased apparent oral bioavailability and decreased apparent oral clearance. Those subjects taking CsA and concomitant efavirenz (EFV) showed time dependent increases in exposure due to ~30% increases in apparent oral bioavailability over time as well as decreased apparent oral clearance, while subjects on TAC and EFV showed time-dependent changes in all PK parameters. The increased bioavailability was not observed in patients on CsA and nevirapine (NVP). These differences between IS drugs and the changes in PK parameters are not easily predicted, illustrating the importance of continued therapeutic drug monitoring in these patients on these complex medication regimens.

An Update on Heart Transplantation in Human Immunodeficiency Virus–Infected Patients

“…Given their effect on CYP3A4 (described earlier), some ARV drugs are subject to formidable pharmacological interactions, many of which are clinically relevant, when coadministered with immunosuppressive agents (36). In the case of non-nucleoside reverse transcriptase inhibitors, efavirenz can decrease calcineurin inhibitor levels.…”

“…In the case of non-nucleoside reverse transcriptase inhibitors, efavirenz can decrease calcineurin inhibitor levels. Consequently, doses of these agents should be increased (36,37). Data on the effect of etravirine are lacking, although rilpivirine does not seem to affect clearance of calcineurin inhibitors (33).…”

“…In contrast, no clinically important interactions are expected between immunosuppressive drugs and nucleoside reverse transcriptase inhibitors, entry inhibitors (enfuvirtide/maraviroc) or nonboosted integrase inhibitors (raltegravir/dolutegravir). In any case, monitoring of both immunosuppressive and ARV agents is critical after HT, and treatment should be optimized bearing in mind the rapid change in plasma levels secondary to unpredictable interactions between ARVs and immunosuppressive agents (36).…”

Advancing Transplant Care in AIDS: Encouraging Innovation in Transplantation

“…On the recipient side, regimens effective at preventing reinfection of liver allografts revived liver transplantation for hepatitis B (HBV). Highly active antiretroviral (HAART) therapies have paved the way for transplantation of organs of all types into patients with human immunodeficiency virus (HIV) infection (1,2). On the donor side, the routine use of increasingly sensitive molecular diagnostic assays in conjunction with the development of US Public Health Service guidelines for donor screening has facilitated the acceptance of organs from donors who meet criteria for increased risk of infection transmission through transplantation.…”

Kidney Transplantation in HIV-Infected Recipients

“…11 Protease inhibitors are significant substrates and inhibitors of CYP3A4 and also the p-glycoprotein efflux system. 12 Calcineurin inhibitors are substrates and inhibitors of CYP3A4 and substrates and inhibitors of p-glycoprotein. Not only would the two be predicted to have significant initial drug interactions when given together, but this interaction may actually change over time or vary depending on the exact antiretroviral and immunosuppression regimen used.…”