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Novel Lopinavir/Ritonavir Sprinkle Formulation for Children in Resource-Limited Settings

By Polly Clayden

July/August 2012

Suitable formulations for infants and young children in resource-limited settings are still urgently needed.

The Indian generic manufacturer, Cipla, has been developing a coformulated twice-daily sprinkle formulation of lopinavir/ritonavir (LPV/r), using melt extrusion technology, and stored in delivery capsules with 40/10 mg per capsule.

Bioequivalence data for the sprinkles versus the innovator syrup in healthy adults were presented earlier this year at CROI and showed, for LPV, the pharmacokinetic (PK) parameters AUC0-t and AUC 0-IFN fell within the conventional bioequivalence range of 80 -125%, while for Cmax it was just outside. For ritonavir (RTV), AUC0-t and Cmax fell just outside the range but AUC 0-IFN was within it. The differences were modest, and based on this pilot PK study, the sprinkle formulation is now being studied in HIV-infected children in the Children with HIV in Africa -- Pharmacokinetics and Adherence of Simple Antiretroviral Regimens (CHAPAS-2) trial conducted in Uganda.1

In a late breaker oral presentation at the 4th International Workshop on HIV Pediatrics, Rosette Keishanyu from the CHAPAS-2 group presented preliminary findings from the trial.2

The objectives were to determine and compare the PK of LPV/r in the sprinkle formulation versus 1) twice daily, coformulated, 100/25 mg paediatric tablet (Cipla) in children 4 to 13 years of age and <25 kg and 2) twice daily, coformulated, 80/20 mg per mL oral solution (Abbott) in infants 3 months to <1 year of age.

In addition the study collected acceptability data comparing the formulation preferences of sprinkles versus tablets among older children and carers and sprinkles versus oral solution among infants' carers.

Cohort 1 enrolled 29 children with a median age of 6.2 years at baseline 55% were girls. Cohort 2 enrolled 14 infants with a median age of 6 months and 57% were girls.

CHAPAS-2 was a randomised cross-over study. Four weeks after randomisation, intensive PK plasma sampling was performed 0,1,2,4,6,8,12 hours after observed intake of a regimen of LPV/r plus two nucleosides (given with food). The children were dosed in accordance with WHO 2010 weight band table dosing. They were then switched to the alternate formulation and PK sampling was repeated at week 8. LPV concentrations were determined using high-performance liquid chromatography. See tables 1 and 2 for PK results presented as geometric means (GM) and geometric mean ratios (GMR).

Subtherapeutic trough levels (<1.0 mg/L) were reported in 4(16%)/1(4%) sprinkles/tablets, (p=0.35), and 0(0%)/3(27%) sprinkles/oral formulation, (p=0.21).

There was high variability with all formulations.


Table 1: Tablets Versus Sprinkles 4 to 13 Years
PK Parameter Tablets GM (95% CI) Sprinkles GM (95% CI) Sprinkles: Tablets GM (90% CI) Historical Data in Children*
AUC0-12h (h*mg/L) 115.6 (103.3-129.8) 83.1 (66.7-103.5) 0.72 (0.60-0.86) 72.6 (41.5-103.7)
Cmax (mg/L) 13.9 (12.9-15.1) 10.3 (8.6-12.2) 0.74 (0.64-0.85) 8.2 (5.3-11.1)
C12h (mg/L) 4.4 (3.3-5.9) 2.6 (1.7-4.1) 0.59 (0.43-0.81) 3.4 (1.3-5.5)

* >2 years receiving steady state LPV/r 230mg/m2 twice daily oral solution.


Table 2: Oral Solution Versus Sprinkles
PK Parameter Oral Solution GM (95% CI) Sprinkles GM (95% CI) Sprinkles: Oral Solution GM (90% CI) Historical Data in Children*
AUC0-12h (h*mg/L) 62.5 (35.6-109.7) 70.9 (41.8-120.2) 1.13 (0.62-2.06) 72.6 (41.5-103.7)
Cmax (mg/L) 9.3 (6.2-13.9) 9.1 (6.1-13.7) 0.98 (0.65-1.49) 8.2 (5.3-11.1)
C12h (mg/L) 2.1 (0.9-5.1) 3.4(2.1-5.7) 1.62(0.67-3.96) 3.4(1.3-5.5)

* >2 years receiving steady state LPV/r 230mg/m2 twice daily oral solution.


The investigators collected acceptability data from questionnaires administered at weeks 0, 4, 8 and 12. The children and/or carers choose which formulation to continue with at week 8.

In cohort 1, older children already established on tablets preferred tablets, particularly as they had a better taste and 22/29 (76%) chose to continue with tablets. Porridge and honey were commonly given with the sprinkles. Several caregivers mentioned the number of capsules they had to open to deliver the dose for the older children.

In cohort 2, the sprinkles were easier to swallow than the oral solution. The majority of the infants (83%) were breastfed. The caregivers also found transport and storage much easier with this formulation and for this age group 10/14 (71%) chose to continue with the sprinkles.

At baseline 41% of caregivers in cohort 1 and 50% of caregivers in cohort 2 thought they would prefer sprinkles.

Virological response data was not shown in this presentation and is awaited.

A cross-over study in cohort 3 (1 to 4 year olds) comparing oral solution to sprinkles is ongoing.


Comment

Cipla have been working on the "Lopimune" sprinkle formulation of LPV/r for a while now,1,3 so it is good to see this promising data in children from CHAPAS-2. Collecting acceptability data together with PK is critical in infants, children and their carers and these findings once again underline the importance of getting the formulation right from this point of view (including the taste).

At the DNDi/IAS-ILF satellite, DNDi announced a new collaboration with Cipla to develop an optimised first-line regimen of a fixed-dose combination of Lopimune Sprinkles, with one of two nucleoside backbones (either ABC/3TC or AZT/3TC). This will be a 4-in-1 combination sachet product, in which the four antiretrovirals will be formulated in taste-masked sprinkles. The partnership will also develop an
adapted 4-in-1 sachet with LPV/r dosed at 1:1 for superboosting when ART is given with TB treatment.

The programme also includes additional support for Chapas-2 cohort 3 (1-4 years old), a superboosting study, plus PK and efficacy studies using currently available ARV formulations (sprinkles of LPV/r and dispersible tablets of NRTIs).

The aim is to gain approval by 2015, to make the product affordable in the public sector in poor countries and to assist with registration and implementation.


References

  1. HTB. Paediatric formulations of ARVs: including an exciting new class. 1 April 2012.
  2. Keishanyu R et al. Pharmacokinetics and acceptability of a new generic lopinavir/ritonavir sprinkle formulation compared with syrup/tablets in African, HIV-infected infants and children according to WHO weight-band dose recommendations (CHAPAS-2). 4th International Workshop on HIV Pediatrics 20-21 July 2012. Washington DC. Oral late breaker LB_08.
  3. HTB. Pilot PK study of two generic paediatric formulations of lopinavir/ritonavir vs originator products. 21 April 2010.
  4. Press release 20 July 2012. DNDi and Cipla to Develop 4-in-1 Paediatric Antiretroviral Drug Combination.

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