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.
Correspondence to: Quirine Fillekes, MSc, Department of Pharmacy, Radboud University Medical Centre, PO Box 9101, 6500 HB Nijmegen, the Netherlands (e-mail: Q.Fillekes@radboudumc.nl).
CHAPAS-2 was supported by the Monument Trust, London, United Kingdom (grant ID: MON4951) and by the Drugs for Neglected Diseases initiative (DNDi), Geneva, Switzerland. Drugs were provided by Cipla Pharmaceuticals, Mumbai, India.
The authors have no conflicts of interest to disclose.
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V.M., Q.F., and A.K. were joint first authors.
Received October 08, 2013
Accepted January 17, 2014