Use of Modelling to Predict Pediatric Dosing of Long-Acting Antiretrovirals

Physiologically based pharmacokinetic (PBPK) modeling can help predict dosing strategies for long-acting (LA) antiretrovirals, according to data presented at CROI 2016.

LA antiretrovirals could provide an important option for children and adolescents. LA regimens have the potential to simplify regimens, reduce drug costs and improve adherence to both treatment and PrEP.

Pediatric dose optimisation is complicated due to differences in anatomical and physiological processes compared with adults. PBPK modelling is a mathematical approach to predict pharmacokinetics (PK) using the description of molecular and physiological processes defining drug disposition. This modelling can be used to identify promising pediatric dosing strategies.

Rajith Jajoli and colleagues from the Department of Molecular and Clinical Pharmacology at University of Liverpool showed data from a study designed to simulate the PK of LA antiretrovirals in children and adolescents and predict optimal doses using PBPK modelling.

The investigators integrated in vitro PK data from cabotegravir (CBV) and rilpivirine (RPV) into their models. These models were validated against available clinical data for the doses of LA formulations in adults: 800 mg CBV and 900 mg RPV. The investigators extrapolated the rate of drug release from injection sites for the two drugs from clinical data in adults.

The anatomy and physiology of children aged 3-18 years was validated against data available in the literature. World Health Organization (WHO) weight band recommendations were used. The investigators simulated PK for 200 pediatric patients for each weight band after intramuscular (IM) injection of LA CBV and RPV.

They validated weights and blood flow rates of children and adolescents at different ages using available anatomical and anthropometric data. And they validated parameters of existing available adult IM formulations of CBV and RPV against available clinical data.

According to the models, mean values for 800 mg CBV quarterly IM injection were: AUC 4467 vs 5257 ug.h/mL, Cmax 3.3 vs 3.54 ug/mL and Ctrough 1.1 vs 1.2 ug/mL. Mean values for 900 mg IM RPV monthly administration were: AUC 74,420 vs 91,087 ng.h/mL, Cmax 168 vs 168.7 ng/mL and Ctrough 79.1 vs 78.3 ng/mL.

The models predicted optimal antiretroviral doses with which at least 95% of patients achieved Ctrough over the cut-off values for quarterly CBV or monthly RPV IM injections. Table 1 shows predicted CBV and RPV doses for all WHO weight bands.

Table 1: Optimised Doses of CBV and RPV LA Formulations for WHO Weight Bands
Age (years)Weight (kg)RilpivirineCabotegravir
Duration1 month3 months
Cut-off limit (ng/mL)20.3 (PAIC90)80 (MEC)166 (PAIC90)664 (MEC)
3-5.7514-19.918072030110
5.75-7.7520-24.919072030130
7.75-9.425-29.919073035150
9.4-10.7530-34.920073535160
10.75-11.935-39.920077045170
11.9-12.840-44.921079045180
12.8-13.745-49.922081050190
13.7-14.7550-54.922582550200
14.75-15.7555-59.923084055210
15.75-17.2560-64.924086055220
17.25-19.565-69.924088060240

The investigators noted that the roles of transporters, the immune system, and drug diffusion through the lymphatic system during long-term treatment are potential limitations that they did not consider in these PBPK models.

But they conclude that PBPK models can help predict dosing strategies and could provide innovative ways to optimise dose requirements in special populations such as pediatrics.

Reference

Rajoli RKR et al. Predicting utility of long-acting injectables in pediatric patients with PBPK models. Conference on Retroviruses and Opportunistic Infections. 22-26 February 2016. Boston. Poster abstract 442.
www.croiconference.org/sessions/predicting-utility-long-acting-injectables-paediatric-patients-pbpk-models-0 (Abstract)
www.croiconference.org/sites/default/files/posters-2016/442_0.pdf (PDF)