Enhanced penetration of indinavir in cerebrospinal fluid and semen after the addition of low-dose ritonavir

Objective: Penetration of antiretroviral drugs into anatomical HIV-1 reserv oirs such as the male genital tract and the central nervous system is impor tant. Data on indinavir (IDV) concentrations in seminal plasma are lacking and IDV concentrations in cerebrospinal fluid are at best borderline. Design: Thirteen patients were treated with zidovudine (or stavudine), lami vudine, abacavir, nevirapine and IDV (1000 mg three times daily). When nevi rapine led to low IDV concentrations, IDV was changed into the combination IDV/ritonavir (RTV) 800/ 100 mg twice daily to improve the pharmacokinetic profile of IDV. Methods: A serum pharmacokinetic profile, a semen sample and a cerebrospina l fluid sample were collected at weeks 8, 24, 48 and 72. Results: Addition of RTV increased the median IDV trough concentration in s erum from 65 to 336 ng/ml (P = 0.005). Median IDV concentration in seminal plasma increased from 141 to 1634 ng/ml (P = 0.002) (n = 9) and in cerebros pinal fluid from 39 (n = 12) to 104 (n = 7) ng/ml (P<0.001). In six patient s with samples collected both before and after the addition of RTV the IDV concentration in seminal plasma increased 8.2 times [95% confidence interva l (CI) 5.2-11.6], and in cerebrospinal fluid 2.4 times (95% CI 1.8-3.9). Conclusions: IDV penetrates well into the male genital tract. The addition of low-dose RTV not only increases IDV concentrations in serum but also in seminal plasma and cerebrospinal fluid, thereby probably improving the pote ncy of the regimen in these anatomical HIV reservoirs. Higher serum trough levels alone can not sufficiently explain the observed increases in seminal plasma and cerebrospinal fluid concentrations. Inhibition of P-glycoprotei n-mediated transport by RTV might be an additional mechanism. (C) 2000 Lipp incott Williams & Wilkins.