721 
Non-linear Pharmacokinetics of High-dose Recombinant Fusion Protein CD4-IgG2 Observed in HIV-1-infected Children
W Shearer1, J DeVille2, P Samson3, J Moye4, J Church5, H Spiegel6, T Fenton3, M Smith7, B Graham8, Courtney V. Fletcher*9, and Pediatric AIDS Clinical Trials Group, National Institutes of Health, Bethesda, MD, USA
1Baylor Coll of Med, Houston, TX, US; 2Univ of California, Los Angeles, US; 3Statistical & Data Analysis Ctr, Harvard Sch of Publ Hlth, Boston, MA, US; 4Natl Inst of Child Hlth and Human Devt, NIH, Bethesda, MD, US; 5Keck Sch of Med, Children's Hosp Los Angeles and Univ of Southern California, US; 6Children's Natl Med Ctr, Washington, DC, US; 7NIAID, NIH, Bethesda, MD, US; 8Frontier Sci & Tech Res Fndn, Amherst, NY, US; and 9Univ of Colorado Hlth Sci Ctr, Denver, US
Background: Doubling the dose
of rC4-IgG (10 mg/kg to 20 mg/kg) in HIV-1-infected children failed to enhance
its anti-viral effects, suggesting non-linear pharmacokinetic behavior.
Methods: Study subjects (n = 13) were perinatally
HIV-1-infected children, 2 to 12 years of age, receiving stable ART for at
least 3 months, with RNA of ³10,000
copies/mL. Descriptive statistics were used to
summarize the results. Kruskal-Wallis tests and
non-parametric analyses were used to test for significance (α=0.05).
Results:
Protein CD4-IgG2 (PRO 542) (20 mg/kg) was given
intravenously at 4 weekly intervals to 13 HIV-1-infected children. This doubled
dose of PRO 542 did not boost the anti-viral effect of PRO 542 at 10 mg/kg given
previously to 6 children. Pharmacokinetic analysis of serum samples yielded the
following median and range values AUC (area under the curve), 11,714 (5964 to
17,870) mg/hour/mL;
clearance, 1.71 (1.12 to 3.35) ml/hour/kg; T½ (half-life), 1.82
(1.22 to 2.43) days; Cmax (maximum
concentration), 337 (84.8 to 517.8) mg/mL; and C-7 days (concentration
7 days after last dose), 8.77 (1.90 to 22.32) mg/mL. Except for a clearance of
0.88 (0.76 to 1.17) mL/hour/kg (p = 0.0009), these values were not appreciably different from those
obtained at a dose of PRO 542 at 10 mg/kg.
Conclusions: Increased clearance of PRO 542 at 20 mg/kg is likely due to
increased high affinity Fc:FcgR binding, increased apparent volume of distribution, and
saturation of the transport (Brambell) receptor (FcRB) at high concentrations of PRO 542. The non-linearity
in PRO 542 pharmacokinetics (an inherent property of iron-based fusion
proteins) is likely responsible for the lack of higher dose effect in
HIV-1-infected children. Our findings have relevance to numerous other fusion
proteins in pediatric medicine where enhancing efficacy by increasing the dose
is desired.
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