Drop in trough blood concentrations of tacrolimus after switching from nelfinavir to fosamprenavir in four HIV-infected liver transplant patients

Abstract

Solid organ transplantation in HIV-infected individuals requires concomitant use of immunosuppressants and antiretrovirals that may cause significant drug interactions. Here we report on a peculiar pharmacokinetic interaction between tacrolimus and protease inhibitors (PIs) which occurred in four HIV-infected liver transplant patients who had to shift PI therapy from nelfnavir to fosamprenavir as a consequence of regulatory restrictions. After the switch, tacrolimus trough blood concentrations significantly dropped in all patients (mean ±sd 6.9 ±2.6 versus 3.2 ±2.0 ng/ml before and after the switch, respectively; P=0.01), so that a marked dosage increase was needed (0.29 ±0.14 versus 0.88 ±0.48 mg/day, 1–3 days before and 3 weeks after the switch, respectively; P=0.046) to attain the desired target (8.7 ±2.3 ng/ ml). Consistently, marked changes of the concentration/dose ratio of tacrolimus were observed in all cases (27.2 ±9.7 ng/ml per mg/kg/day versus 9.7 ±4.0 ng/ml per mg/kg/day before and after the switch, respectively; P<0.001). Our findings suggest that fosamprenavir may be less potent than nelfinavir in inhibiting tacrolimus clearance and support the need for higher tacrolimus dosage to avoid insufficient immunosuppression in HIV-infected liver transplant patients when switching from nelfinavir to fosamprenavir or even when directly starting antiretroviral therapy with fosamprenavir.