Pharmacokinetic studies in very young infants

3 June 2009. Related: Conference reports, Paediatric care, CROI 16 (Retrovirus) 2009.

Polly Clayden, HIV i-Base

The World Health Organization (WHO) recommends ARV treatment for all HIV-infected infants <12 months old, and that this should be started as early as possible. [1]

Nevirapine (NVP)-based ART is recommended for infants with no perinatal NVP exposure from mother-to-child transmission prophylaxis or NNRTI-based maternal ART. Protease inhibitor-based ART, usually lopinavir/ritonavir (LPV/r), is recommended for NNRTI-exposed infants.

There is however a scarcity of pharmacokinetic (PK) data on which to base dosing to support these recommendations. Two posters at CROI provided useful data for NVP and LPV/r in this age group.

Nevirapine exposure infants weighing 3-6kg receiving paediatric fixed dose combinations

A study conducted by Veronica Mulenga and coworkers from the CHAPAS trial in Zambia, looked at PK in infants weighing 3-6kg receiving fixed dose combination tablets. [2]

This group had previously reported data from a 12-hour PK study of nevirapine (NVP), stavudine (d4T) and lamivudine (3TC) receiving Triomune Baby (50mg NVP, 6mg d4T and 30mg 3TC) and Triomune Junior (double Baby dose). These tablets were developed with higher ratios of NVP to NRTI doses, according to paediatric dosing recommendations, to prevent under dosing of NVP. [3]

This earlier evaluation only included two children weighing 3-6kg, therefore the investigators performed a further PK sub-study of 14 children weighing 3-6kg.

The sub-study enrolled 16 children >1month of age and eligible for treatment in accordance with WHO guidelines. Children were initiated on full-dose NVP with a target dose of 300mg/m2. Target doses for d4T and 3TC were 2 mg/kg and 8 mg/kg respectively. With these targets, children in the WHO 3-6kg weightband receive one tablet twice daily. [4]

Samples were taken at t=0, 2, 6 and 12 hours after an observed dose, within four weeks of starting Triomune Baby.

One child was excluded because of non-adherence. Among the remaining 15 children there were 8 girls and 7 boys with a median (IQR) age of 5.3 months (4.1-8.4) and weight of 5.3kg (4.2-5.5). The children’s daily doses were 348 mg/m2 (324-386), 2.3 mg/kg (2.2-2.9) and 11.3 mg/kg (10.9-14.2) for NVP, d4T and 3TC respectively. See table 1 for PK parameters.

Table 1. PK parameters children 3-6kg

Mean (IQR), [standard deviation]

The investigators found large interpatient variability in Cmin concentrations of NVP.

When these data were compared with PK parameters from the previous study of children >6kg there was a difference of 15-20% lower NVP exposure in the 3-6kg weight band. d4T and 3TC parameters were comparable to the higher weight bands.

The investigators noted that 4/15 (27%) children had sub-therapeutic levels of NVP Cmin(<3.0mg/L compared to 3/63 >6kg (p=0.02). This occurred most frequently in children <5 months (3/6, 50%) vs >5 months (1/9, 11%) but the number of children was too small for this to reach statistical significance. The dose range in the younger children was 324-406 mg/m2 daily.

They suggest that the clinical consequences of NVP exposure may be minor as infants will be <5 months for a short time after treatment initiation, but that this requires further evaluation.

Model predicts rapid increase in lopinavir exposure in infants <6 months

Mina Nikanjam and coworkers performed a population PK analysis to characterise changes in lopinavir/ritonavir (LPV/r) PK in maturing young infants, and to assess dosing in this population. [5]

This group had previously shown that LPV/r exposure in infants <6 weeks of age receiving 300mg/75mg/m2 12 hourly, is lower than in older children receiving recommended doses. [6] However, the exact age at which LPV PK becomes similar to that in older populations is poorly understood.

This analysis used PK data from 31 infants <6 weeks of age from a prospective study, IMPAACT/PACTG P1030 to evaluate a 300mg/75mg/m2 12 hourly dose. 12 hour PK profiles (pre, 2, 4, 8 and 12 hr) were performed at week 2 of treatment and at 1 year of age.

Infants who did not achieve target LPV exposure at week 2 (Cpre >1mcg/mL) received a modified dose and a repeat analysis after 2 weeks. Trough LPV concentrations were taken regularly for up to 4 years and determined using LC/MS/MS method.

The investigators developed a population PK model using 549 LPV concentrations using NONMEM non-linear regression software and allometric weight scaling. Empiric post hoc LPV PK parameter estimates were generated from visits with multiple samples. The final model used Monte Carlo simulations to estimate appropriate LPV dosing in this infant population.

The investigators reported that age to was a powerful predictor of apparent clearance (CL/F), and was best described as a non-linear co-variate for bioavailability (F). They found half-life to be less affected by age. Ritonavir (RTV) levels correlated with LPV levels.

The interpatient variability for CL and volume of distribution (V) were 31.6% and 42.9% respectively. The median CL/F decreased with increasing age: 0.34 (<3 months, n=17), 0.22 (3-6months, n=19), 0.13 (approx 1 year, n=26) L/h/kg. As did the median V/F: 3.2 (<3 months), 2.4 (3-6 months) and 1.4 (approx 1 year) L/h/kg. The median AUC increased with increasing age: 49.8 (<3 months), 67.1 (3-6 months) and 11.10 (approx 1 year) mcg*hr/mL. Based on this model LPV AUC in a typical infant would reach the adult value of 80mcg*hr/mL by 9 months of age.

Monte Carlo simulations predicted very low troughs of LPV (<1 ug/mL) occurring with the study dose with 20% frequency in infants <3months but <1% in older infants. Using new WHO weightband dosing recommendations, the model predicted a lower frequency (13%) of troughs <1 ug/mL in the very young infants.

The investigators suggested that LPV concentration increases during the infants’ first year are likely to be due to increased bioavailability. Also the rapid increase in LPV exposure was likely to account for overall good virological suppression observed (most infants achieved viral load <400 copies/mL at 48 weeks) despite low concentrations at the start of therapy.

Comment

Both studies suggest large interpatient variability in exposure in young infants, but that this may be of little clinical consequence (and clearly things get easier as the children get older).

The introduction of food with LPV/r may play a significant role in increasing the absorption as the infants mature. However, there are probably some developmental issues relating to pancreatic exocrine function that also contribute to this.

The WHO dosing guidelines were constructed with the doses “rounded-up” and represent on average larger doses that the FDA labelled dose, which will counter the reduced absorption to some degree.

Although the investigators recommend frequent monitoring in young infants, the clinical response in the earlier LPV/r study provides the rationale for LPV/r use in resource-limited settings where this is not available.

Healthcare workers should be cautious of mal-absorption in infants with diarrhoea as well as in those that do not experience a clinical improvement.

Suitable solid paediatric formulations also make treating children more feasible. The fixed dose combination tablets used in CHAPAS are dispersible and can therefore be used in even the youngest infants in place of oral formulations. The investigators have not reported problems, according to Zambian health workers, and they are popular with families, as they are easy to carry. Of note, this study initiated the children with full dose NVP, which meant there was no change of dosing at two weeks after starting treatment.

Urgently required now is an easier to use, store and transport paediatric formulation of LPV/r. Cipla (who also produce Baby and Junior Triomune) have developed a “sprinkle” formulation using melt extrusion technology (similar to the newer LPV/r tablets). The formulation is in the same 4:1 drug ratio in 100/25 mg sachets. This is appropriate for even the youngest children, as it allows the drug to be easily mixed in with food. PK studies are currently planned or underway.

References:

1. WHO Antiretroviral Therapy for Infants and Children 2008. Report of the WHO Technical Reference Group, Paediatric HIV/ART Care Guideline Group Meeting WHO Headquarters, Geneva, Switzerland, 10-11 April 2008.
   http://www.who.int/hiv/pub/paediatric/WHO_Paediatric_ART_guideline_rev_mreport_2008.pdf
2. Mulenga et al. Pharmacokinetics of nevirapine in 3- to 6-kg, HIV-infected infants taking pediatric fixed-dose combination tablets. 16th CROI, 2009. Poster abstract 881.
   http://www.retroconference.org/2009/Abstracts/34683.htm
3. L’homme et al. Nevirapine, stavudine and lamivudine pharmacokinetics in African children on fixed dose combination tablets. AIDS 2008: 22(5), 557-559.
4. WHO Summary of Paediatric Dosing.
   http://www.who.int/hiv/paediatric/Sum_WHO_ARV_Ped_ARV_dosing.pdf
5. Nikanjam et al. Lopinavir population pharmacokinetic model and dose simulation predicts rapid increase in exposure for HIV-infected infants initiating therapy at <6 months of age. 16th CROI, February 2009, Montreal, Canada. Abstract 880.
   http://www.retroconference.org/2009/Abstracts/34368.htm
6. Carrarelli et al. Lopinavir pharmacokinetic maturational changes and variability in HIV-infected infants beginning Kaletra therapy at <6 weeks of age. 15th CROI, February 2008, Boston, MA, USA. Abstract 573.
   http://www.retroconference.org/2008/Abstracts/31505.htm