Exposure-response relationships for saquinavir, zidovudine, and zalcitabine in combination therapy.
The relationship of CD4+ cell response, level of RNA in plasma, and quantitative peripheral blood mononuclear cell (PBMC) titer to apparent drug exposure was investigated by using data from AIDS Clinical Trial Group protocol 229, a multicenter randomized study. Patients received either saquinavir, zalcitabine, or a combination of both, along with open-label zidovudine. Approximately 100 patients were enrolled in each arm, and the primary study duration was 24 weeks. Individual drug exposure, the area under the concentration-time curve, was estimated by using population-based pharmacokinetic methods. Response was defined as the maximum increase in CD4+ cell count or the maximum decrease in RNA in plasma or PBMC titer adjusted for baseline CD4+ cell count, RNA in plasma, and PBMC titer, respectively. Regression of responses on exposure demonstrated an exposure effect for saquinavir which was significant for the maximum increase in CD4+ cell count and the decrease in RNA in plasma. For the PBMC titer, no significant relationship could be demonstrated but the results suggested a trend similar to that of the other response variables. For all three response variables, the slope of the saquinavir exposure response was greater with the triple combination (saquinavir, zidovudine, and zalcitabine) than with the combination of saquinavir and zidovudine, suggesting possible synergism between saquinavir and zalcitabine.
Vanhove
G F
GF
Division of Clinical Pharmacology, Stanford University, California, USA.
Gries
J M
JM
Verotta
D
D
Sheiner
L B
LB
Coombs
R
R
Collier
A C
AC
Blaschke
T F
TF
D000328:Adult; D019380:Anti-HIV Agents / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D018791:CD4 Lymphocyte Count / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D008297:Male; D008875:Middle Aged; D012367:RNA, Viral / Q000097:blood; D019258:Saquinavir / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016047:Zalcitabine / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015215:Zidovudine / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*
D019380:Anti-HIV Agents; D012367:RNA, Viral; D015215:Zidovudine; D016047:Zalcitabine; D019258:Saquinavir