Relationships between exposure to saquinavir monotherapy and antiviral response in HIV-positive patients.
OBJECTIVE
The aim of this study was to confirm the most appropriate dosage of a new soft gelatin capsule (SGC) formulation of the HIV protease inhibitor saquinavir by investigating the relationships between systemic (plasma) exposure to saquinavir and plasma HIV RNA and CD4+ cell counts using empirical mathematical modelling.


METHODS
A randomised, non-blind, multicentre, dose-ranging 8-week study of monotherapy with 400, 800 or 1200 mg of saquinavir-SGC or 600 mg of the hard gelatin capsule (HGC) formulation, both administered 3 times daily, was carried out in protease inhibitor-naive, HIV-positive adults. Two surrogate markers of response, plasma HIV RNA level and CD4+ cell count, were fitted to 2 measures of systemic drug exposure, the area under the plasma concentration-time curve (AUC) and trough plasma concentration (Cmin), using 6 exposure-response models of progressively increasing complexity. Akaike and Schwarz model selection criteria were applied to determine the most effective pharmacokinetic-pharmacodynamic relationship.


RESULTS
A total of 88 patients were randomised; pharmacokinetic and pharmacodynamic data were available for 84 patients. In terms of plasma HIV RNA, pharmacokinetic-pharmacodynamic relationships were best described by a 2-parameter maximum effect (Emax) model, which predicted a typical maximum reduction in viral load of 1.94 log10 copies/ml [coefficient of variation (CV) 12%], with a half-maximal antiviral response occurring at a Cmin of 50 micrograms/L (CV 40%). Saquinavir-SGC 1200 mg administered 3 times daily produced a median AUC to 24 hours (AUC24) of approximately 20,000 micrograms/L.h, corresponding to 85% of the maximum achievable antiviral effect as defined by the model. None of the models yielded a satisfactory fit for CD4+ cell count.


CONCLUSIONS
Empirical mathematical modelling confirmed that, when administered 3 times daily, the optimum dose of saquinavir-SGC is 1200 mg, corresponding to 3600 mg/day.
Gieschke
R
R
F. Hoffmann-La Roche, Basel, Switzerland.
Fotteler
B
B
Buss
N
N
Steimer
J L
JL
D000328:Adult; D019540:Area Under Curve; D018791:CD4 Lymphocyte Count / Q000187:drug effects; D002214:Capsules; D004334:Drug Administration Schedule; D005260:Female; D006678:HIV / Q000187:drug effects / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D006679:HIV Seropositivity / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008962:Models, Theoretical; D012367:RNA, Viral / Q000097:blood; D019258:Saquinavir / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*
D002214:Capsules; D017320:HIV Protease Inhibitors; D012367:RNA, Viral; D019258:Saquinavir