726   Pharmacokinetics (PK) of Selected Doses of T-20, a Fusion Inhibitor, in HIV-1- Infected Children.

B. Kosel*¹, J. Church², C. Cunningham³, P. Sista⁴, F. Aweeka¹, and the PACTG P1005 Study Team.
¹Univ. of California at San Francisco;²Children's Hosp. of Los Angeles;³SUNY, Upstate Med. Univ., Syracuse, NY; and⁴Trimeris, Inc., Durham, NC.

Background:T-20, a 36-amino-acid synthetic peptide, inhibits HIV by binding to envelope glycoprotein gp41 at a region critical for virus-target cell fusion. There is no information on the PK and optimal dosing of T-20 in the pediatric population. Based upon preliminary adult PK, doses were chosen so that expected plasma concentrations would bracket the target level of 1,000 ng/ml for effective viral suppression. This is the first pediatric Phase I/II study to evaluate PK of three different doses of T-20 by intravenous (IV) and subcutaneous (SQ) routes. Part B of the study will evaluate chronic SQ dosing in the same population.

Methods:Subjects were 3—12 years of age, on stable antiretroviral therapy for at least 16 weeks, with plasma HIV RNA >10,000 copies/ml. Three cohorts of four (n = 12) children received a single SQ injection of T—20 at 15 mg/m², 30 mg/m², or 60 mg/m², followed by 12-hour PK on day 0. The same subjects received identical single IV bolus injections on day 1 (24 hours after SQ dose), followed by 12-hour sampling. T-20 was measured by an immunoassay using two anti-T-20 mouse monoclonal antibodies. PK analysis was done for both routes of administration using selected models in the WinNonlin program.

Results:Due to single-dose kinetics, area under the curve to infinity (AUC_INF) was identified. AUC_INFwas extrapolated for all subjects. AUC_INFmean (CV%) for the 15, 30, and 60 mg/m²IV single-dose administrations were 13883 (45), 30027 (61), and 36531 (26) ng*hr/ml, respectively. Mean (CV%) AUC_INFfor the 15, 30, and 60 mg/m²SQ single-dose administrations were 10,166 (85), 18,292 (22), and 50,804 (12) ng*hr/ml, respectively. All subjects in the SQ 60 mg/m²cohort achieved plasma levels at hour 12 above 1000 ng/ml with a mean (CV%) of 1810 (22) ng/ml.

Conclusions:Total drug exposure for the two lower-dose IV cohorts was greater than the respective SQ, but plasma drug exposure was greatest in the SQ 60 mg/m²cohort. All subjects administered the SQ 60 mg/m²dose achieved 12-hour troughs above the target level of 1,000 ng/ml, which justifies twice-daily SQ administration.