HTB South

Pharmacokinetics of lopinavir/ritonavir in combination with rifampicin based TB treatment in children

Polly Clayden, HIV i-Base

Lopinavir/ritonavir (LPV/RTV) is first line treatment for young children in South Africa. Concomitant treatment for TB is common in children with HIV. There is a complicated interaction between this boosted protease inhibitor and the first line TB drug, rifampicin (RIF), which reduces the bioavailabilty and Cmin of LPV by approximately 75% and 99% respectively.

Two strategies are possible to increase the LPV levels when it is dosed with RIF – either increasing the dose of RTV to a LPV:RTV 4:4 ratio or doubling the dose to a LPV:RTV ratio 8:2.

Chao Zhang and colleagues from the University of Cape Town showed a population pharmacokinetic (PK) model developed to describe the interactions between LPV, RTV and RIF in children. They used this to look at the effect of various factors (age, BSA, weight, gender, haemaglobin, albumin, ALT) on LPV and RTV PK, and make dosing recommendations for HIV/TB coinfected children receiving these drugs concurrently. [1]

In this study, 39 children with HIV only received the standard dose of LPV/RTV, 4:1, (control group); 15 coinfected children received the super-boosted dose, 4:4; and 20 the double dose, 8:2. Then 11 coinfected children received the standard dose following RIF-based treatment. Repeated sampling was performed (4-6 from each child) up to 12 hours post dose.

The children were a median age of 21 months (range 6 months to 4.5 years) and a medium weight of 10.2kg (range 5-17kg).

Using a one-compartment model with first order absorption for LPV and a one-compartment model with transit absorption for RTV, the investigators modelled the effect of RTV concentration on LPV clearance as direct inhibition with an Emax model.

The investigators found that, during concomitant treatment with RIF, the relative oral bioavailability of LPV was reduced by 79% in children receiving the twice the standard dose of LPV/RTV. RTV clearance was 18 L/h with RIF and 13L/h without.

The estimated baseline clearance of LPV, when there was no detectable RTV was 4.34 L/h. As the concentrations of RTV increased, the clearance of LPV decreased in a sigmoid relationship (EC 50, 0.051 mg/L). They found volume of distribution for LPV and RTV were 11.7 and 102 L respectively.

When the investigators performed simulations for dose optimisation during RIF-based TB treatment with a target of LPV concentrations with Cmin >1mg/L in 95% of children, they predicted doses of LPV/RTV as described in Table 1. They noted that smaller children required higher mg/kg doses of LPV/RTV, in both 4:1 and 1:1 ratios, than larger children.

Table 1: Simulation for dose optimistion of LPV/RTV during RIF-based TB treatment

Body weight LPV:RTV 4:1 LPV:RTV 1:1
12 hourly LPV dose (mg/kg) 8 hourly LPV dose (mg/kg) 12 hourly LPV dose (mg/kg)
4-6 kg 50 25 20
6-8 kg 42 22 17
8-12 kg 37 21 15
12-18 kg 30 18 12

comment

The same group previously presented data to show that the double dose LPV/r is not sufficient for children when coadministration with rifamipicin. [2]

The current median LPV dose using double dose strategy in this study is 23 mg/kg,

The investigators suggestion for dose adjustment in this study is much higher than double dose. Or they suggest switching to an 8 hourly dose strategy considering the adverse effect slinked to higher doses. [3]

References:

  1. Zhang C et al. Population pharmacokinetics of lopinavir and ritonavir in combination with rifampicin-based antitubercular treatment in HIV-infected children. 10th International Congress on Drug Therapy in HIV Infection, November 7-11. Glasgow. Oral abstract O24. Published in Journal of the International AIDS Society 2010 13(Suppl 4). O223.
    http://www.jiasociety.org/content/13/S4/O24
  2. McIlleron et al. Double-dose lopinavir/ritonavir provides insufficient lopinavir exposure in children receiving rifampicin-based anti-TB treatment. 16th CROI. February 2009, Montreal. Oral abstract 98.
    http://www.retroconference.org/2009/Abstracts/34615.htm
  3. Personal communication with the author.

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