The pharmacokinetics and acceptability of lopinavir/ritonavir minitab sprinkles, tablets, and syrups in african HIV-infected children.
BACKGROUND
Guidelines recommend lopinavir/ritonavir (LPV/r) as first- and second-line therapy for young and older HIV-infected children, respectively. Available formulations have limitations making their widespread use complex.


METHODS
An open-label comparative bioavailability (randomized crossover) study compared a novel twice-daily minitab sprinkle formulation (40 mg/10 mg, Cipla Pharmaceuticals) versus innovator syrup in HIV-infected Ugandan infants aged 3 to <12 months (cohort A) and children aged 1-4 years (cohort B) and versus Cipla tablets (100/25 mg) in children aged 4 to <13 years (cohort C). Twelve-hour intensive pharmacokinetic sampling after observed LPV/r intake (plus 2 nucleoside reverse transcriptase inhibitors) following World Health Organization 2010 dosing with food was performed 4 weeks after enrollment. Children then switched formulation; sampling was repeated at week 8. Acceptability data were also collected.


RESULTS
Seventy-seven infants/children were included in cohort A (n = 19)/B (n = 26)/C (n = 32). Among 132 evaluable pharmacokinetic profiles, there were 13/21/25 within-child comparisons in cohort A/B/C. For minitabs versus syrup, geometric mean [95% confidence interval (CI)] AUC0-12h was 88.6 (66.7-117.6) versus 77.6 (49.5-121.5) h·mg/L in cohort A [geometric mean ratio (GMR) (90% CI) = 1.14 (0.71 to 1.85)] and 138.7 (118.2 to 162.6) versus 109.1 (93.7 to 127.1) h·mg/L in cohort B [GMR (90% CI) = 1.27 (1.10 to 1.46)]. For minitabs versus tablets, geometric mean (95% CI) AUC0-12h was 83.1 (66.7 to 103.5) versus 115.6 (103.0 to 129.7) h·mg/L; GMR (90% CI) = 0.72 (0.60 to 0.86). Subtherapeutic levels (<1.0 mg/L) occurred in 0 (0%)/2 (15%) minitabs/syrup in infants (P = 0.48), no children aged 1-4 years and 4 (16%)/1 (4%) minitabs/tablets (P = 0.35). About 13/17 (76%) and 19/26 (73%) caregivers of infants and children aged 1-4 years, respectively, chose to continue minitabs after week 8, mainly for convenience; only 7/29 (24%) older children (five <6 years) remained on minitabs.


CONCLUSIONS
LPV/r exposure from minitabs was comparable with syrup, but lower than tablets, with no significant differences in subtherapeutic concentrations. Minitabs were more acceptable than syrups for younger children, but older children preferred tablets.
*Joint Clinical Research Centre, Kampala, Uganda; †Department of Pharmacy, Radboud University Medical Centre, Nijmegen, the Netherlands; ‡Baylor College of Medicine Children's Foundation Uganda, Mulago Hospital Kampala, Kampala, Uganda; §MRC Clinical Trials Unit at University College London, London, United Kingdom; and ||Drugs for Neglected Diseases Initiative, Geneva, Switzerland.
Victor
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Musiime
Quirine
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Fillekes
Adeodata
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Kekitiinwa
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Kendall
Rosette
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Keishanyu
Rachel
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Namuddu
Natalie
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Young
Wilfred
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Opilo
Marc
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Lallemant
A Sarah
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Walker
David
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Burger
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D000293:Adolescent; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D016001:Confidence Intervals; D018592:Cross-Over Studies; D004339:Drug Compounding; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D007223:Infant; D061466:Lopinavir / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D019438:Ritonavir / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013607:Tablets / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014454:Uganda; D014944:World Health Organization
D019380:Anti-HIV Agents; D013607:Tablets; D061466:Lopinavir; D019438:Ritonavir