730   Both Short-Term Virological Efficacy and Drug- Associated Nephrotoxicity Are Related to Indinavir (IDV) Pharmacokinetics (PK) in HIV-1- Infected Thai Patients.

D. Burger*¹, M. Felderhof², P. Phanupak³, C. Duncombe^3,4, A. Mahanontharit³, W. Yeamwanichnun³, S. Ubolyam³, D. Cooper⁴, M. Stek⁵, J. Lange², and P. Reiss².
¹Univ. Med. Ctr., Nijmegen, The Netherlands;²Acad. Med. Ctr./ IATEC, Amsterdam, The Netherlands;³HIV-NAT, Thai Red Cross AIDS Res. Ctr., Bangkok, Thailand;⁴NCHECR, Sydney, Australia; and⁵Merck & Co, Whitehouse Station, NJ.

Background:The PK of IDV 800 mg q8h and its relationship with pharmacodynamics (PD, e.g. efficacy and toxicity) has been well described for Caucasian HIV-infected patients, but information for other races is lacking.

Methods:Nineteen HIV-1-infected patients who participated in one arm of the HIV-NAT 005 study (AZT + 3TC + IDV 800 mg q8h) recorded an 8-h PK curve 4 weeks after starting treatment. Receiver operating characteristic (ROC) curves were used to explore relationships between IDV PK parameters and PD. Virological response was defined as having a viral load of <50 copies/mL at week 24. Nephrotoxicity was defined as flank pain, hematuria, or an increase in serum creatinine of >25% (up to week 12).

Results:The median (+ IQR) body weight of the 19 patients (6 females and 13 males) was 60.5 (52.7—67.5) kg. Median + IQR values for indinavir AUC_0—8h, C_maxand C_minwere 20.9 (13.1—27.0) mg/L per h, 8.1 (6.6—9.4) mg/L and 0.13 (0.09—0.27) mg/L, respectively. These values are not different from values found in Caucasian patients. Correlations between body weight and indinavir pharmacokinetic parameters were (borderline) significant for C_max(r²0.27; p = 0.02) and AUC (r²0.19; p = 0.06), but not for C_min(r²0.00; p = 0.94). Women had lower body weights than men (median: 50.1 vs 63.7 kg; p = 0.005), corresponding with non-significant trends of higher C_maxand AUC in women vs. men. ROC curves showed that breakpoints in IDV PK parameters for predicting virological failure were 14 mg/L per h for AUC_0—8h, 7 mg/L for C_max, and 0.10 mg/L for C_min(p = 0.025; Pearson's Chi-square). Breakpoints in IDV PK parameters for predicting nephrotoxicity were 30 mg/L per h for AUC_0—8h(p = 0.036; Pearson's Chi-square) and 10 mg/L for C_max. C_minwas not related to nephrotoxicity.

Conclusions:IDV PK and PD in Thai HIV-1-infected patients are similar to those described in Caucasian patients, despite an overall lower body weight in the Thai population. Both short-term virological efficacy and drug-associated nephrotoxicity are related to IDV PK parameters.