AEGiS-13IAC: Steady-state pharmacokinetics (PK) of saquinavir (SQV) with and without two doses of itraconazole in HIV-1+ Thai patients:HIV NAT001.2 substudy.

13th International AIDS Conference

Durban, South Africa - July 9-July 14, 2000

Steady-state pharmacokinetics (PK) of saquinavir (SQV) with and without two doses of itraconazole in HIV-1+ Thai patients:HIV NAT001.2 substudy.

Int Conf AIDS 2000 Jul 9-14; 13:(abstract no. WeOrB545)

Cardiello P, Kroon E, Hoetelmans R, Vorarien W, Ubolyam S, Phanuphak P, Lange J, Cooper D, Ruxrungtham K
P. Cardiello, HIV-NAT, The Thai Red Cross Aids Research Centre, 104 Rajdumri Road, Pathumwan, Bangkok 10400, Thailand, Tel.: +66 2 255 73 34, Fax: +66 2 252 57 79, E-mail: peter.c@chula.ac.th

BACKGROUND: It was shown that 200 mg of itraconazole qd increases SQV concentrations (hard gelatin capsule, HGC) by 5-fold. In HIV NAT 001.2 the effect of 2 doses of itraconazole (100 and 200 mg qd) on SQV PK was investigated when using SQV soft gelatin capsules (SGC).

METHODS: HIV-1-infected patients from HIV NAT001.2 received 2 nucleoside reverse transcriptase inhibitors (AZT/3TC or d4T/ddI) and 1400 mg bid SQV-SGC. Patients were randomized to no, 100, or 200 mg itraconazole qd. In 17 patients steady-state PK of SQV were determined after 4 weeks therapy during 12 hours. SQV plasma concentrations were determined just before, and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, and 12 hours after taking drugs by a sensitive and validated RP-HPLC methodology. A non-compartmental model was applied to calculate area under the plasma concentration versus time curve (AUC), maximum (Cmax) and minimum (Cmin) concentration, time to Cmax (Tmax) and elimination half-life (t1/2).

RESULTS: The median (IQR) steady-state PK parameters for SQV in the 3 arms are: 0 mg itraconazole qd in 6 patients resulted in AUC0-12(h*mg/L) = 4.93 (3.44-7.51), Cmax = 1.37 mg/L (0.71-1.72), Tmax = 2.0h (1.9-3.0), Cmin = 0.13 mg/L (0.05-0.15) and t1/2 = 5.0h (3.4-11.8); 100 mg itraconazole qd in 5 patients resulted in AUC = 6.93 (4.47-10.26), Cmax = 1.90 (0.86-2.83), Tmax = 3.0 (1.8-3.0), Cmin = 0.09 (0.06-0.17) and t1/2 = 3.6 (2.3-4.2): 200 mg itraconazole qd in 6 patients resulted in AUC = 6.13 (3.86-14.76), Cmax = 1.51 (0.82-3.29), Tmax = 2.0 (1.8-3.2), Cmin = 0.09 (0.05-0.19) and t1/2 = 2.8(2.1-4.8). No significant SQV PK parameter differences were found with Kruskal-Wallis 1-way ANOVA (p>0.15).

CONCLUSION: Steady-state exposure to SQV (SGC) in plasma is not significantly enhanced with 100 or 200 mg of itraconazole qd, as was found for the HGC formulation (5-fold increase with 200 mg itraconazole).

Keywords: AEGIS, Saquinavir, HIV-2, HIV-1, HIV Infections, Area Under Curve, Didanosine, Reverse Transcriptase Inhibitors, Itraconazole, Half-Life, Stavudine, Biological Availability, Zidovudine, Lamivudine, Gelatin, Human, pharmacokinetics
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