Steady-state pharmacokinetics and 48-week safety and antiviral activity of fosamprenavir/ritonavir twice-daily regimens in HIV-infected children 4 weeks to <2 years old: results of APV20002, a prospective, open-label, multicenter cohort study

Purpose: Pharmacokinetics, safety and antiviral activity of fosamprenavir/ritonavir (FPV/RTV) twice daily (BID) were evaluated in protease inhibitor (PI)-naive and -experienced HIV-1-infected children aged 6mo-<2y (Cohort-1) and 4wks-<6mo (Cohort-2) primarily from South Africa and Mexico.

Methods: Intensive pharmacokinetic sampling was performed at Wk2 or 8; pre-dose samples were collected every 4-12wks.  Safety and plasma HIV-1 RNA were monitored every 4-12wks.

Results: 59 HIV-1-infected children received ≥1 dose of FPV/RTV; 54 were included in the intent-to-treat-exposed (ITT[E]) population (28 in Cohort-1, 26 in Cohort-2). Median FPV exposure was 640d (range 8-1093d), with 78% exposed >48wks.  Plasma APV PK parameters, as geometric means (GM) with 95% confidence intervals and ratios of GM pediatric values to historical adult values (HAV), are shown in the table.  

APV PK parameter	HAV	6mo-<2y (Cohort-1)/fraction of HAV	4wk-<6mo (Cohort-2)/fraction of HAV
	700/100mg BID,N=159	45/7mg/kg BID,N=10	45/10mg/kg BID,N=9
AUC(0-τ)(h.μg/mL)	37.0 (35.1,38.9)	27.5 (14.5,52.1)/0.744	26.6 (15.2,46.8)/0.720
Cmax(μg/mL)	5.62 (5.35,5.92)	5.84 (3.35,10.2)/1.04	6.25 (3.82,10.2)/1.11
Cτ (μg/mL)	2.17 (2.05,2.30)(n=158)	2.17 (1.69,2.80)(n=29)/1.00	0.860 (0.500,1.48)(n=11)/0.397
CL/F(mL/min/kg)	3.52 (3.33,3.71)(n=157)	22.8 (12.0,43.1)/6.47	22.9 (12.9,40.6)/6.51

At Wk48, 64% (18/28) of Cohort-1 and 58% (15/26) of Cohort-2 achieved HIV-1 RNA <50copies/mL (ITT[E], Snapshot analysis). Nine children experienced analysis plan defined virologic failure. Median increase from baseline in CD4⁺cell percentages at Wk48 was 5% in both cohorts. Drug-related Gr2-4 AEs occurred in 12/59 (20%) children; the most frequent were increased cholesterol (5/59,8%) and gastroenteritis (2/59,3%). Twenty-two children experienced serious AEs (SAEs), of which three were considered drug-related. Three children died following SAEs.

Conclusion: FPV/RTV dosing regimens provided plasma APV exposures in Cohort-1 comparable to those reported in FPV/RTV-treated adults. APV Cτ was lower in Cohort-2 but clinical outcomes were comparable. The overall safety profile in children aged <2y was similar to that observed in older children and adults.