Association of Saquinavir Plasma Concentrations with Side Effects but Not with Antiretroviral Outcome in Patients Infected with Protease Inhibitor-Susceptible Human Immunodeficiency Virus Type 1

Abstract

The objective of this study was to identify parameters among saquinavir pharmacokinetics, patients' demographics or comedications, to be addressed for improved personalized therapy. The presence of human immunodeficiency virus type 1 (HIV-1) RNA at therapy week 48 (principal target parameter), CD4 cell count at week 48, infections and side effects during 48 weeks, indicators of liver toxicity and lipid abnormalities at week 48, and a 12-h saquinavir plasma concentration-versus-time profile were assessed in 56 patients receiving saquinavir-ritonavir (1,000 and 100 mg, respectively) twice daily (44 therapy-naïve and 12 antiretrovirally pretreated patients) for association with saquinavir plasma concentrations, demographics, baseline values of target parameters, and coadministered antiretrovirals. Antiretroviral failure was observed in 8 of the 56 patients in whom HIV-1 RNA was detectable at week 48. This therapeutic failure was not associated with individual saquinavir pharmacokinetics. More likely, therapeutic failure was related to incidences interfering with antiretroviral therapy, causing therapy interruptions or incompliance. Weak associations were, however, seen between high maximum saquinavir plasma concentrations and both CD4 counts of >200 cells l ؊1 at week 48 (P ‫؍‬ 0.014) and constitutional side effects during 48 weeks (P ‫؍‬ 0.002). However, patients with high CD4 counts and constitutional side effects were not identical (P ‫؍‬ 0.53). Saquinavir therapeutic drug monitoring in patients infected with protease inhibitor-susceptible HIV-1 taking saquinavir-ritonavir (1,000 and 100 mg, respectively) is not demanded for improving the antiretroviral effect. It may be contemplated in cases with constitutional side effects or low CD4 counts with weak immune responses.

Cytochrome P450 3A Inhibition by Atazanavir and Ritonavir, but Not Demography or Drug Formulation, Influences Saquinavir Population Pharmacokinetics in Human Immunodeficiency Virus Type 1-Infected Adults

“…Antiretrovirally effective plasma concentrations above the in vitro 90% inhibitory concentration of 5 to 80 nM (12) are clinically obtained by decreasing saquinavir's metabolic clearance (CL) following coadministration of 100 mg of the cytochrome P450 3A (CYP3A) blocking agent ritonavir (4,7,8). However, too-low or too-high concentrations jeopardize the therapy success or produce side effects, respectively (10,13). Therefore, factors affecting plasma saquinavir concentrations are of clinical relevance.…”

“…(A subset of these data was published previously [10].) Population pharmacokinetics is receiving increasing acceptance for exploration and definition of relevant sources of variation in drug exposure and responses (1).…”

“…However, too-low or too-high concentrations jeopardize the therapy success or produce side effects, respectively (10, 13). Therefore, factors affecting plasma saquinavir concentrations are of clinical relevance.(A subset of these data was published previously [10].) Population pharmacokinetics is receiving increasing acceptance for exploration and definition of relevant sources of variation in drug exposure and responses (1).…”

Prolonged Exposure to Lopinavir Impairs Endothelium-dependent Hyperpolarization-mediated Relaxation in Rat Mesenteric Arteries

“…34 The concentrations that demonstrated relaxing effects in the present experiments can be reached in the plasma of HIV-infected patients, albeit with high therapeutic doses (Table 3). [15][16][17][18][19][20][21][22] Theoretically, vasodilatation may occur in patients on these PIs and NNRTIs, and care should be taken with the prescription of high doses of these compounds because of unwanted reductions in peripheral resistance. This may pose a risk in patients receiving antihypertensive therapies.…”

“…The concentration of the PIs and NNRTIs used in the organ chambers ranged from 10 29 to 10 25 M, because these were the clinically relevant concentrations, that is corresponding to the plasma concentrations monitored after oral intake of these drugs in humans. [15][16][17][18][19][20][21][22] Triton X-100 was purchased from Pharmacia Biotech (Uppsala, Sweden). ACh, indomethacin, levcromakalim, L-NAME, TRAM-34, and UCL-1684 were purchased from Sigma Chemicals Co (St Louis, MO).…”