Pharmacokinetics, safety, and antiviral activity of fosamprenavir-containing twice-daily regimens in HIV-infected children 2 to 18 years old: report from APV29005, a 48-week prospective, open-label, multicenter cohort study

Purpose: Amprenavir (APV) pharmacokinetics, safety and antiviral activity with unboosted fosamprenavir (FPV) and ritonavir (RTV)-boosted FPV BID were evaluated in protease inhibitor (PI)-naive and -experienced HIV-1-infected children aged 2-18y.

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

Results: 109 HIV-1-infected children (2-5y[n=39], 6-11y[n=30], 12-18y[n=40]) received ≥1 dose of FPV (±RTV), 88% exposed >48w. Twenty PI-naïve children 2-5y received FPV BID and 89 received FPV/RTV BID. In children aged 2-5y administered FPV 30 mg/kg BID(n=9), geometric mean(GM;95%CI) plasma APV AUC(0-t) was 22.3 (15.3,32.6)h.μg/mL, Cmax 7.15 (5.05,10.1)μg/mL, Ct 0.552 (0.406,0.750)μg/mL(n=19), and CL/F 19.3 (13.2,28.2)mL/min/kg.  These values were 1.27-, 1.41-, 1.90-, and 1.23-fold higher than respective historical values reported in adults administered FPV 1400mg BID (n=189). Pharmacokinetic findings with the FPV/RTV regimen are shown in the table.  

APV Parameter	FPV/RTV BID*
	2-5y	6-11y	12-18y
	23/3 mg/kg BID,N=14	18/3 mg/kg BID,N=12	700/100mg BID,N=13
AUC(0-τ),h.μg/mL	55.3 (37.9,80.7)	48.4 (38.1,61.4)	35.3 (28.2,44.1)
Cmax,μg/mL	8.66 (6.08,12.3)	6.40 (5.02,8.15)	4.93 (3.83,6.34)
Cτ,μg/mL	3.39 (2.51,4.57)(n=16)	2.42 (1.90,3.07)(n=23)	2.01 (1.74,2.32)(n=40)
CL/F,mL/min/kg	6.06 (4.12,8.91)	5.27 (4.16,6.68)	5.33 (4.23,6.68)
*GM (95% CI); PK values were within 0.876-1.72-fold range of historical values in adults treated with FPV/RTV 700/100mg BID.

At Wk48, 60% (12/20) of the PI-naïve children on FPV and 73% (36/49) on FPV/RTV achieved HIV-1 RNA <400c/mL, versus 48% (19/40) of PI-experienced children on FPV/RTV (intent-to-treat-exposed, snapshot analysis). Median CD4+ cell percentages increased 6-10% by Wk 48.  Twenty-five children experienced analysis plan-defined virologic failure.  Drug-related Gr2-4 AEs occurred in 12/109 (11%), including vomiting (3/109, 3%), diarrhea and AST increases (each 2/109, 2%).  Eighteen children experienced serious AEs, 9 with suspected abacavir hypersensitivity.

Conclusion: FPV-containing regimens provided APV exposures in 2-to-18-year-old children comparable to exposures reported with FPV regimens approved in adults.  The safety profile was also similar. Virologic suppression was maintained over 48 wks.