18 July 2009 The 1st International Workshop on HIV Pediatrics Cape Town, South Africa

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A Novel Pediatric Fixed-Dose Combination (FDC) of Zidovudine (ZDV), Lamivudine (3TC), Nevirapine (NVP): Pharmacokinetics and Safety in HIV-Infected Thai Children 18 July 2009 The 1st International

1 A Novel Pediatric Fixed-Dose Combination (FDC) of Zidovudine (ZDV), Lamivudine (3TC), Nevirapine (NVP): Pharmacokinetics and Safety in HIV-Infected Thai Children 18 July 2009 The 1st International Workshop on HIV Pediatrics Cape Town, South Africa Wasana Prasitsuebsai 1, Tim R. Cressey 2,3, Nirun Vanprapar 1, Edmund Capparelli 4, Linda Aurpibul 5, Virat Sirisanthana 5, Chanin Limwongse 1, Petronella Muresan 3, Achara Eksaengsri 6, Elizabeth Smith 7, Kenneth McIntosh 3, Ram Yogev 8 and Kulkanya Chokephaibulkit 1 for the IMPAACT P1069 team 1 Siriraj Hospital, Bangkok, Thailand, 2 PHPT-IRD, Chiang Mai University, Thailand, 3 Harvard School of Public Health, MA, USA, 4 University of California, San Diego, CA, USA, 5 RIHES, Chiang Mai University, Chiang Mai, Thailand, 6 Thai Government Pharmaceutical Organization, Bangkok, Thailand, 7 Pediatric Medicine Branch, Division of AIDS, National Institute of Allergy and Infectious Diseases, MD, USA, 8 Chicago Children s Memorial Hospital, Chicago, IL, USA O_05

2 HIV/AIDS Milestones in Thailand First case diagnosis AZT monotherapy dual therapy (AZT+ddI/ddC) HAART GPO-VIR Z250 used in children GPO-VIR Z250 (AZT/3TC/NVP) Access to Care Program GPO-VIR S30/40 (d4t/3tc/nvp) GPO-VIR S30 used in children GPO-VIR S7 study in children

3 Antiretroviral Therapy in Thai Children (as of June 5th, 09) 20% AZT+3TC+NVP 43% AZT+3TC+NVP GPOvir-Z (250/150/200mg) Other Regimens d4t+3tc+nvp 68% 1136 children d4t+3tc+nvp GPOvir-S (30/150/200mg) 37% 94% 2860 children * Total 8276 children on ARV

4 Problem with using adult FDC If base on NVP dosage, patient will have lower dosage of AZT and 3TC Tablets need to be cut into ¼, ½, or ¾ for young children, accuracy of pill cutting is uncertain Adult FDC GPO-VIR S30 or GPO-VIR Z250

5 Background There is an urgent need for affordable, safe, quality ARV formulations for pediatric use, particularly fixed dose combinations (FDC). [WHO; Technical Summary 2006] Using d4t causes a large proportion of metabolic side-effects. It suggested the consideration to replace d4t with with zidovudine containing regimens. [WHO; Scaling up ART 2007] d4t free FDCs are needed as alternative treatments for children to improve their quality of life.

6 Background Zidovudine Lamivudine Nevirapine ZDV/ 3TC/ NVP 30/ 15 / 28 mg

7 Study Schema P1069 is a ongoing phase I/II, randomized, open-label, multiple-dose comparative PK cross-over study. (NCT ; Study Population: HIV-infected children 5 months (20 weeks) to <13 years of age clinically stable on a HAART regimen (NVP+2 NRTIs) for at least 4 wks Primary Objectives To compare the bioavailability of ZDV/3TC/NVP in GPO-VIR Z30 with the liquid drug formulations To estimate the population average exposure to NVP with GPO-VIR Z30 and to compare this to an adult exposure of therapeutically adequate NVP concentration.

8 Study Schema Subjects are stratified into four dosage groups based on body weight: Group 1: 6-8 kg (n= 5-8) Group 2: >8-16 kg (n= 9-12) Group 3: >16-23 kg (n= 9-12) Group 4: >23-30 kg (n= 8-12) * Total 44 children Study Duration 2 weeks on GPO-VIR Z30 tablet(s) 2 weeks on the ZDV, 3TC and NVP liquid formulations 4 weeks of Safety follow-up.

9 Study Design Arm A Day 14 PK GPOvir-Z30 ZDV+3TC+NVP Liquids Day 0 Randomization Direct Observation of Therapy was performed for the 72 hours prior to the PK study. Blood drawn at pre-dose, 0.5, 1, 2, 4, 8, and 12 hours postdose Day 28 PK ZDV+3TC+NVP Liquids GPOvir-Z30 Arm B Day 14 PK *Dose: equivalent dose to the fixed-dose combination based on weight

10 Table 1: GPO-VIR Z30 Dose per Body Weight and Corresponding Liquid Formulation Doses Group Weight (kg) GPOVIR Z30 Tablets/dose ZDV dose (10 mg/ml) Liquid Formulations 3TC dose (10 mg/ml) NVP dose (10 mg/ml) Total kg 2 >8-16 kg 3 >16-23 kg 4 >23-30 kg tabs 6.0 ml 3.0 ml 5.6 ml 14.6 ml tabs 9.0 ml 4.5 ml 8.4 ml 21.9 ml > tabs 9.0 ml 4.5 ml 8.4 ml 21.9 ml tabs 12.0 ml 6.0 ml 11.2 ml 29.2 ml > tabs 12.0 ml 6.0 ml 11.2 ml 29.2 ml tabs 15.0 ml 7.5 ml 14.0 ml 36.5 ml tabs 18.0 ml 9.0 ml 16.8 ml 43.8 ml > tabs 18.0 ml 9.0 ml 16.8 ml 43.8 ml tabs 21.0 ml 10.5 ml 19.6 ml 51.1 ml

11 Figure 1: Comparison of Dose per m 2 or kg for GPO-VIR Z30 tablets and WHO Guidelines for pediatric FDC of AZT(60mg)/3TC(30mg)/NVP(50mg) Schedule for ideal antiretroviral products WHO 2007; Technical Work Group Zidovudine Lamivudine Nevirapine ZDV/3TC/NVP FDC ratio of 60/30/55 mg was recommended by WHO

12 Results 11 children had PK sampling performed for this initial analysis Gender Male Female ARM A (n=6) ARM B (N=5) Total (n=11) GPO-VIR Z30 / ZVD+3TC+NVP LIQ ZVD+3TC+NVP LIQ / GPO-VIR Z30 / 2 4 Age (yrs) 8 (5-11) 7 (0.6-11) 7 (0.6-11) Weight (kg) 22 (16-29) 20 (10-18) 21 (10-29) CD4 Percent 32 (23-45) 34 (32-49) 32 (23-49) Table 1: Baseline Demographics (n=11)

13 Figure 2: Mean (SD) concentration vs. time curves for the GPO-VIR Z30 Pediatric tablet and Liquid formulation (n=11) Zidovudine Lamivudine Nevirapine

14 Figure 2: Individual subject AUC for the GPO-VIR Z30 Pediatric tablet and Liquid formulation (n=11) Zidovudine Lamivudine Nevirapine

15 Results AUC (mcg*hr/ml) ZDV 3TC NVP Target AUC % - 200% of Target 1.40 to to to AUC (90% CI) 1.40 to to to The criteria for therapeutic inadequacy were not met for any of the 3 drugs. No serious drug-related toxicity was reported during the 4 weeks of follow up.

16 Pharmacogenomic Results 5 children were CYP2B6 516 G>T heterozygous including the child with highest NVP AUC level 11 children had the wild type allele at position 1459 (C/C)

Conclusion GPO-VIR Z30 pediatric tablet met both safety and therapeutically adequate criteria This preliminary report suggests that the new GPO-VIR Z30 FDC tablet is safe and achieves target plasma

17 Conclusion GPO-VIR Z30 pediatric tablet met both safety and therapeutically adequate criteria This preliminary report suggests that the new GPO-VIR Z30 FDC tablet is safe and achieves target plasma levels in Thai HIV-infected children weighing kg but more patients, particularly <10 kg, are needed to fully assess this new FDC tablet. The study in ongoing. As of June 2009, 33 from 44 children were enrolled into this study. There was no SAE occurred.

18 Acknowledgements We would like to thank all the children who participated in the IMPAACT P1069 trial and the study staff conducting the protocol at the sites. This study was supported by the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) funded by the National Institute of Allergy and Infectious Diseases, National Institutes of Health. Grants number(s): U01 AI Thai Government Pharmaceutical Organization (GPO)

A Novel Chewable Pediatric Fixed-Dose Combination (FDC) of Zidovudine (ZDV), Lamivudine (3TC), Nevirapine (NVP): Pharmacokinetics and Safety in HIV-Infected Thai Children Thank You Wasana

Cressey 2,3, Nirun Vanprapar 1, Edmund Capparelli 4, Linda Aurpibul 5, Virat Sirisanthana 5, Chanin Limwongse 1, Petronella Muresan 3, Achara Eksaengsri 6, Elizabeth Smith 7, Kenneth McIntosh 3, Ram

19 A Novel Chewable Pediatric Fixed-Dose Combination (FDC) of Zidovudine (ZDV), Lamivudine (3TC), Nevirapine (NVP): Pharmacokinetics and Safety in HIV-Infected Thai Children Thank You Wasana Prasitsuebsai 1, Tim R. Cressey 2,3, Nirun Vanprapar 1, Edmund Capparelli 4, Linda Aurpibul 5, Virat Sirisanthana 5, Chanin Limwongse 1, Petronella Muresan 3, Achara Eksaengsri 6, Elizabeth Smith 7, Kenneth McIntosh 3, Ram Yogev 8 and Kulkanya Chokephaibulkit 1 for the IMPAACT P1069 team 1 Siriraj Hospital, Bangkok, Thailand, 2 PHPT-IRD, Chiang Mai University, Thailand, 3 Harvard School of Public Health, MA, USA, 4 University of California, San Diego, CA, USA, 5 RIHES, Chiang Mai University, Chiang Mai, Thailand, 6 Thai Government Pharmaceutical Organization, Bangkok, Thailand, 7 Pediatric Medicine Branch, Division of AIDS, National Institute of Allergy and Infectious Diseases, MD, USA, 8 Chicago Children s Memorial Hospital, Chicago, IL, USA 18 July 2009 The 1st International Workshop on HIV Pediatrics Cape Town, South Africa

Pediatric ARV Working Group Dosing Recommendations

Pediatric ARV Working Group Dosing Recommendations Overall Goals To develop pediatric weight band dosing for ARVs that would simplify dosing and produce therapeutic drug exposure Recommend dosing strengths