The use of pharmacokinetically guided indinavir dose reductions in the management of indinavir-associated renal toxicity.

OBJECTIVES: Indinavir is associated with nephrotoxicity. Therapeutic drug monitoring of indinavir improves clinical outcome, but there is little data regarding therapeutic drug monitoring for patients with established indinavir-associated renal impairment. We prospectively studied the use of therapeutic drug monitoring in patients with virological success but established nephrotoxicity on an indinavir-containing regimen. METHODS: We measured indinavir C(trough)/C(2h), serum creatinine, pyuria, blood pressure (BP), weight and HIV RNA. The major endpoint of interest was the number of patients achieving a normal creatinine level 20 weeks following final indinavir dose adjustment. Primary analysis was by intention to treat (ITT). RESULTS: A total of 35 patients were enrolled; mean (SD) age 40.3 (5.8) years; mean (SD) BMI 21.5 (2.8) kg/m(2). At baseline 6/35 (17%) had a serum creatinine concentration within normal limits, but were offered enrolment because of previous nephrotoxicity (nephrolithiasis and/or abnormal serum creatinine), and a screening pharmacokinetic profile associated with increased nephrotoxicity risk. By ITT analysis 11/35 (31%) had normal creatinine at study end (P = 0.18). Of the 29 patients with abnormal creatinine at baseline, 7/29 (24.1%) had normal creatinine at study end (P = 0.016). Patients had a median (IQR) indinavir per dose adjustment over the study of 400 (400-800) mg. We observed improvements in estimated creatinine clearance, pyuria, resting BP and indinavir pharmacokinetic profile. HIV RNA control was maintained with continued immune recovery despite lower indinavir doses. CONCLUSIONS: Patients experiencing nephrotoxicity on an indinavir-containing regimen were safely maintained on indinavir by means of therapeutic drug monitoring. Parameters of renal function improved but did not return to baseline values, at least in the short-term