739   Amprenavir (APV) and Ritonavir (RTV): Intraindividual Comparison of Different Doses and Influence of Concomitant NNRTI on Steady-State Pharmakokinetics in HIV-Infected Patients.

O. Degen*¹, M. Kurowski², J. Van Lunzen¹, C. K. Schewe¹, and H.-J. Stellbrink¹.
¹Univ. Hosp. Eppendorf, Hamburg and²Auguste Viktoria Krankenhaus, Berlin, Germany.

Background:RTV is known to increase APV drug levels. An optimum dose of both drugs in combination remains to be defined.

Methods:Steady-state PK of 450 mg APV and 200 mg RTV BID in 17 HIV-infected patients using liquid chromatography/mass spectometry (LC-MS). All received concomitant RTI treatment, 10 had additionally efavirenz (EFV), 2 also had nevirapine (NVP) and 5 had no NNRTI. In 5 of the NNRTI-treated patients, intraindividual comparisons of steady-state PK to 600 mg APV and 100 mg RTV BID were performed.

Results:Steady-state PK of APV 45 0mg and RTV 200 mg BID after median 5 weeks of treatment (range 4— 13). All had high and sustained plasma levels of APV. Without NNRTI the median C_minwas 2094 ng/ml (range 1178—2049), median C_maxwas 6380 ng/ml (range 4265—14,399), and median AUC_0—8was 29888 ng/ml (range 20254—50651). Medians with EFV were C_min2366 ng/ml (range 950—8183), C_max9076 ng/ml (range 4473— 22746), and AUC_0-832314 ng/ml (range 16,990—103,234). The two NVP pts. showed median C_mins of 1101 and 1536 ng/ml, median C_maxs of 11,983 and 5773 ng/ml, and median AUC_0—8s of 56,445 and 21,229 ng/ml. In 5 pts. (4 EFV, 1 NVP) dose was changed to 600 mg APV and 100 mg RTV BID after median 34 weeks (range 24- -48). Steady-state PK median was 28 days after switch (range 21—56). C_mindecreased by 80% to a median of 469 ng/ml (range 169—2030), C_maxby 80% to a median of 1781 ng/ml (range 721-3899), and AUC_0-8by 77% to a median of 7869 ng/ml (range 3610—19,840).

Conclusions:450 mg APV and 200 mg RTV BID shows high and stable plasma levels with or without concomitant NNRTI. The lowest C_minof 950 ng/ml was >3 times above the C_minobserved at the standard dose of 1200 mg BID (320 ng/ml). The intraindividual comparison to 600 mg APV and 100 mg RTV BID shows a decrease of APV plasma level by -80% of C_min, -80% of C_maxand -77% of AUC_0-8. Especially in salvage patients, high plasma levels may be required for optimal virological response; 450 mg APV with 200 mg RTV BID ensures a higher drug exposure in combination with NNRTIs.