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Efavirenz ( EFV)

Plasma efavirenz concentrations in HIV-infected children in Thailand: Comparison between FDA and WHO 2010 dosing guidelines.

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Efavirenz ( EFV)

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  1. Plasma efavirenz concentrations in HIV-infected children in Thailand: Comparison between FDA and WHO 2010 dosing guidelines Nontiya Homkham1,2,3, Saik Urien4,5, Tim R. Cressey1,6,7, ChulapongChanta8, Virat Sirisanthana9, Thition Narkbunnam10, SawitreeKrikajornkitti11, NareeratKamonpakorn12, Lily Ingsrisawang2, Jean Marc Treluyer5, GonzagueJourdain1,6,7 1Institut de Recherche pour le Développement (IRD) UMI 174-PHPT, France, 2Department of Statistics, Faculty of Science, Kasetsart University, Bangkok, Thailand, 3ED 420 Université Paris-Sud 11 - Université Paris Descartes, France 4Unité de Recherche Clinique Paris Centre, Assistance Publique Hôpitaux de Paris, France, 5CIC-0901 Inserm & APHP, EA3620 Université Paris Descartes, France, 6Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand, 7Harvard School of Public Health, USA, 8Chiangrai Prachanukroh Hospital, Chiangrai, Thailand, 9Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand, 10Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand, 11Samutsakhon Hospital, Samutsakhon, Thailand, 12 SomdejPrapinklao Hospital, Bangkok, Thailand Abstract MOAB0104: Plasma efavirenz concentrations in HIV-infected children in Thailand: Comparison between FDA and WHO 2010 dosing guidelines

  2. Efavirenz (EFV) • Efavirenz plus a dual-nucleoside reverse transcriptase inhibitor (NRTI) backbone combination is the preferred first line antiretroviral therapy for HIV-infected children more than 3 years and weighting above 10 kg.1 • Low plasma concentrations have been associated with treatment failure and higher concentrations associated with a higher risk of toxicities.2,3 • A target mid-dose efavirenz concentrations (C12) between 1 and 4 mg/L has been suggested to ensure efficacy and minimizing the risk of toxicities.2 WHO 2010, 2) Marzolini C et al 2001 AIDS, 3) CsajkaC et al 2003 ClinPharmacolTher. 2 Abstract MOAB0104: Plasma efavirenz concentrations in HIV-infected children in Thailand: Comparison between FDA and WHO 2010 dosing guidelines

  3. Pharmacokinetics of efavirenz in children • Two studies in African children have reported high proportions of children with subtherapeutic plasma concentrations of efavirenz • In South Africa, 40% were found to have subtherapeutic concentrations1. • Within a substudy of the ARROW trial, 38% children with EFV C24<1 mg/L2. • In Thailand, a lower percentage of children (15%) had an efavirenz 24-hour postdose concentration (C24) <1.0 mg/mL following current FDA dosing guidelines. • However, the percentage was higher within specific weight bands (50% and 33% in the 15 to <20 kg and 25 to 32.5 kg weight range)3. 1) Ren Y et al 2007 J Acquir Immune DeficSyndr, 2) Fillekes Q et al 2011 J Acquir Immune DeficSyndr, 3) Cressey TR 2013 JAIDS. 3 Abstract MOAB0104: Plasma efavirenz concentrations in HIV-infected children in Thailand: Comparison between FDA and WHO 2010 dosing guidelines

  4. Efavirenz Dosing guidelines in HIV-infected children 4 Abstract MOAB0104: Plasma efavirenz concentrations in HIV-infected children in Thailand: Comparison between FDA and WHO 2010 dosing guidelines

  5. Objective 5 Abstract MOAB0104: Plasma efavirenz concentrations in HIV-infected children in Thailand: Comparison between FDA and WHO 2010 dosing guidelines To evaluate the current FDA and World Health Organization (WHO) 2010 efavirenz dose guidelines for HIV-infected children using a population pharmacokinetic approach.

  6. Study Design 6 Abstract MOAB0104: Plasma efavirenz concentrations in HIV-infected children in Thailand: Comparison between FDA and WHO 2010 dosing guidelines Retrospective analysis of HIV-infected Thai children who received an efavirenz-based regimen • Stored plasma samples from 190 children within the PHPT Observational treatment cohort [NCT00433030], Siriraj Hospital, and RIHES, Chiang Mai University were included in the analysis. • EFV was administered following FDA-bodyweight band recommendations. Assessment of efavirenz concentrations • Efavirenz concentrations were measured at the Faculty of Associated Medical Sciences, Chiang Mai University, using a validated isocratic reversed-phase high-performance liquid chromatography (HPLC) method.

  7. Methods 7 1) Kuhn E et al 2005 Computational Statistics & Data Analysis. Abstract MOAB0104: Plasma efavirenz concentrations in HIV-infected children in Thailand: Comparison between FDA and WHO 2010 dosing guidelines

  8. Methods 8 1) Kuhn E et al 2005 Computational Statistics & Data Analysis. Abstract MOAB0104: Plasma efavirenz concentrations in HIV-infected children in Thailand: Comparison between FDA and WHO 2010 dosing guidelines

  9. Methods 9 1) Kuhn E et al 2005 Computational Statistics & Data Analysis. Abstract MOAB0104: Plasma efavirenz concentrations in HIV-infected children in Thailand: Comparison between FDA and WHO 2010 dosing guidelines

  10. Methods 10 1) Kuhn E et al 2005 Computational Statistics & Data Analysis. Abstract MOAB0104: Plasma efavirenz concentrations in HIV-infected children in Thailand: Comparison between FDA and WHO 2010 dosing guidelines

  11. Results • Characteristics at baseline of HIV-infected children * This patient first received dual NRTI combination zidovudine (ZDV) and lamivudine (3TC) as first line combination before starting efavirenz at the age of 5.4 years. 11 Abstract MOAB0104: Plasma efavirenz concentrations in HIV-infected children in Thailand: Comparison between FDA and WHO 2010 dosing guidelines

  12. EFV Population PK model • 623 efavirenz plasma concentrations from 190 HIV-infected children were included. • A one-compartment model with delay absorption. • Body weight influenced efavirenz CL/F and V/F and allometric scaling significantly reduced interindividual variability. • CL/F = θCL x (BW / 70) 0.75, V/F = θV x (BW / 70) PC-VPC (prediction-correlated visual predictive check) RSE%, relative standard error (standard error of estimate / estimate*100. Abstract MOAB0104: Plasma efavirenz concentrations in HIV-infected children in Thailand: Comparison between FDA and WHO 2010 dosing guidelines

  13. Results 13 Abstract MOAB0104: Plasma efavirenz concentrations in HIV-infected children in Thailand: Comparison between FDA and WHO 2010 dosing guidelines • EFV PK parameter with median (range): • AUC0-24 was 49 (8 to 296) mg/L.hr. • A predicated efavirenz C12 was 2.3 (0.07 to 11.9) mg/L • Among 190 children • 16 children (8%) had predicted C12 below 1 mg/L. • 12 children (6%) had an efavirenz C12 above 4 mg/L, no serious adverse events were reported

  14. Comparison between FDA and WHO 2010 EFV dosing guidelines Dose (mg) 10 to <14 14 to <15 15 to <20 20 to <25 25 to <32.5 32.5 to <35 35 to <40 ≥40 Body weight (kg) [FDA] C12 <1 [FDA] 1<C12<4 [FDA] C12 >4 [WHO2010] C12 <1 [WHO2010] 1<C12<4 [WHO2010] C12 >4 14 Abstract MOAB0104: Plasma efavirenz concentrations in HIV-infected children in Thailand: Comparison between FDA and WHO 2010 dosing guidelines

  15. Comparison between FDA and WHO 2010 EFV dosing guidelines Dose (mg) 10 to <14 14 to <15 15 to <20 20 to <25 25 to <32.5 32.5 to <35 35 to <40 ≥40 Body weight (kg) [FDA] C12 <1 [FDA] 1<C12<4 [FDA] C12 >4 [WHO2010] C12 <1 [WHO2010] 1<C12<4 [WHO2010] C12 >4 15 Abstract MOAB0104: Plasma efavirenz concentrations in HIV-infected children in Thailand: Comparison between FDA and WHO 2010 dosing guidelines

  16. Comparison between FDA and WHO 2010 EFV dosing guidelines Dose (mg) 10 to <14 14 to <15 15 to <20 20 to <25 25 to <32.5 32.5 to <35 35 to <40 ≥40 Body weight (kg) [FDA] C12 <1 [FDA] 1<C12<4 [FDA] C12 >4 [WHO2010] C12 <1 [WHO2010] 1<C12<4 [WHO2010] C12 >4 16 Abstract MOAB0104: Plasma efavirenz concentrations in HIV-infected children in Thailand: Comparison between FDA and WHO 2010 dosing guidelines

  17. Conclusions/Discussion 17 1) PuthanakitTet al 2009 AntivirTher. Abstract MOAB0104: Plasma efavirenz concentrations in HIV-infected children in Thailand: Comparison between FDA and WHO 2010 dosing guidelines • Compared to the FDA dosage guidelines, the WHO 2010 guidelines is expected to: • Reduce the number of children with concentrations below target • However, results in a high percentage of children with concentrations above target associated with high risk of toxicity. • From a previous study on Thai children, the frequency of CYP2B6 TT genotype was found to be 11% (EFV concentration >6 mg/L1). • Several children in our study had EFV concentration >6 mg/L, which may be explained by this genotype. • The model suggests that the EFV drug concentrations seems appropriate but safety data on EFV in children are needed receiving the WHO 2010 weight-band dosing

  18. Acknowledgments We would like to thank all the patients who participated in the study and the study teams at the sites. Support • Institut de Recherche pour le Développement, France • Program for HIV Prevention and Treatment (UMI 174-PHPT) • Faculty of Associated Medical Sciences, Chiang Mai University • Global Fund to fight AIDS, Tuberculosis and Malaria (THA-102-G01-H-00) • Ministry of Public Health, Thailand • Research Institute for Health Sciences, Thailand • Siriraj Hospital, Thailand 18 Abstract MOAB0104: Plasma efavirenz concentrations in HIV-infected children in Thailand: Comparison between FDA and WHO 2010 dosing guidelines

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