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 reservoirs such as the male genital tract and the central nervous system is important. Data on indinavir (IDV) concentrations in seminal plasma are lacking and IDV concentrations in cerebrospinal fluid are at best borderline.


METHODS
Thirteen patients were treated with zidovudine (or stavudine), lamivudine, abacavir, nevirapine and IDV (1000 mg three times daily). When nevirapine 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 cerebrospinal fluid sample were collected at weeks 8, 24, 48 and 72.


RESULTS
Addition of RTV increased the median IDV trough concentration in serum 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 cerebrospinal fluid from 39 (n = 12) to 104 (n = 7) ng/ml (P < 0.001). In six patients with samples collected both before and after the addition of RTV, the IDV concentration in seminal plasma increased 8.2 times [95% confidence interval (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 potency 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-glycoprotein-mediated transport by RTV might be an additional mechanism.
van Praag
R M
RM
National AIDS Therapy Evaluation Center, Department of Internal Medicine, Academic Medical Center, University of Amsterdam, The Netherlands.
Weverling
G J
GJ
Portegies
P
P
Jurriaans
S
S
Zhou
X J
XJ
Turner-Foisy
M L
ML
Sommadossi
J P
JP
Burger
D M
DM
Lange
J M
JM
Hoetelmans
R M
RM
Prins
J M
JM
D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D015224:Dideoxynucleosides / Q000627:therapeutic use; D004197:Disease Reservoirs; D017320:HIV Protease Inhibitors / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics* / Q000627:therapeutic use; D015497:HIV-1 / Q000302:isolation & purification; D006801:Humans; D019469:Indinavir / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D019259:Lamivudine / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D019829:Nevirapine / Q000627:therapeutic use; D012367:RNA, Viral / Q000097:blood / Q000134:cerebrospinal fluid; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use; D019438:Ritonavir / Q000627:therapeutic use*; D012661:Semen / Q000737:chemistry*; D018119:Stavudine / Q000627:therapeutic use; D019562:Viral Load; D015215:Zidovudine / Q000627:therapeutic use; D000099227:Abacavir
D015224:Dideoxynucleosides; D017320:HIV Protease Inhibitors; D019469:Indinavir; D019259:Lamivudine; D019829:Nevirapine; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D019438:Ritonavir; D018119:Stavudine; D015215:Zidovudine; D000099227:Abacavir