Abstract #O_06: Impact of drug transporter genetic polymorphisms on tenofovir exposure and...

Abstract #O_06: Impact of drug transporter genetic polymorphisms on tenofovir exposure and creatinine clearance in HIV-infected Adults in Thailand

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. Cressey 1,6,7, Chulapong Chanta8, Virat Sirisanthana9, Thition Narkbunnam10, Sawitree Krikajornkitti11,

Nareerat Kamonpakorn12, Lily Ingsrisawang2, Jean Marc Treluyer5,

Gonzague Jourdain1,6,7

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 Somdej Prapinklao

Hospital, Bangkok, Thailand

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


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

1) WHO 2010, 2) Marzolini C et al 2001 AIDS, 3) Csajka C et al 2003 Clin Pharmacol Ther.


2


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 Defic Syndr, 2) Fillekes Q et al 2011 J Acquir Immune Defic Syndr, 3) Cressey TR 2013 JAIDS.


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Dose (mg)

Body weight (kg)

FDA dosing guideline

WHO 2006 dosing guideline

WHO 2010 dosing guideline

200 10 to <15 10 to <14 10 to <14

250 15 to <20 14 to <20

300 20 to <25 20 to <25 14 to <25

350 25 to <32.5 25 to <30

400 32.5 to <40 30 to <40 25 to <35

600 ≥ 40 ≥ 40 ≥ 35

Efavirenz Dosing guidelines in HIV-infected children

4


Objective

• To evaluate the current FDA and World Health Organization (WHO) 2010 efavirenz dose guidelines for HIV-infected children using a population pharmacokinetic approach.


5


Study DesignRetrospective 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.


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Methods


Population PK analysis

• Development of the efavirenz pharmacokinetic model was performed using the nonlinear mixed effect modelling software program Monolix version 4.1.1

Fisher exact test

• Using the final model, we used the Fisher exact test to compare: • the proportions of patients with predicted efavirenz concentration 12 hours post-dose

(C12): <1 mg/L, 1 to 4 mg/L and >4 mg/L• HIV RNA viral load below and above 400 copies/mL.

Model

validation

• Visual Predictive Check (VPC)• 200 efavirenz concentration profiles were simulated and compared with the

observed data to evaluate the predictive performance of the model.

Dose simulatio

n

• Monte Carlo simulations were performed to estimate the probability of achieving EFV concentrations within its therapeutic window for children in each of the weight bands between 10 to 50 kg, following the FDA and WHO 2010 dosing guidelines.

1) Kuhn E et al 2005 Computational Statistics & Data Analysis. 7


Methods




Fisher exact test

• Fisher exact test to compare between the proportions of patients with predicted efavirenz concentration 12 hours post-dose (C12): <1 mg/L, 1 to 4 mg/L and >4 mg/L

Model

validation



Dose simulatio

n




Methods




Fisher exact test


Model

validation



Dose simulatio

n




Methods




Fisher exact test


Model

validation



Dose simulatio

n

• Monte Carlo simulations were performed to estimate the probability of achieving EFV concentrations within its therapeutic window, following the FDA and WHO 2010 dosing guidelines.



Results


Characteristics Median (range)Age (years) 7.2 (0.1* to 15.2)

Body weight (kg) 16 (5 to 42)

Height (cm) 110 (59 to 149)

Serum Glutamic Pyruvate Transaminase (IU/L) 31 (5 to 288)

Haemoglobin (g/dL) 10.5 (3.1 to 15)

CD4 (%) 5 (1 to 51)

HIV RNA load (log10 copies/mL) 5.1 (2.8 to 7)

* 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.

Characteristics at baseline of HIV-infected children

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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.


Parameters Mean RSE (%)

Structural model

Mtt (h) 1.59 13

CL/F (L/h/70 kg) 12.1 12

V/F (L/70 kg) 432 6

Statistical model

ωMtt 0.67 13

ωCL/F 0.93 12

ωV/F 0.61 9

σ (mg/L) 0.30 0RSE%, relative standard error (standard error of estimate / estimate*100.

PC-VPC (prediction-correlated visual predictive check)

CL/F = θCL x (BW / 70) 0.75, V/F = θV x (BW / 70)


• 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

Results


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0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

13 14 13 11

62 62 6559

25 24 2230

16 14 16 15

59 62 63 64

25 24 21 21

8 11 12 8

5356 60

50

39 33 2842

[FDA/WHO 2010] C12 <1 [FDA/WHO 2010] 1<C12<4 [FDA/WHO 2010] C12 >4[FDA] C12 <1 [FDA] 1<C12<4 [FDA] C12 >4[WHO2010] C12 <1 [WHO2010] 1<C12<4 [WHO2010] C12 >4

200 250 250 300 350 400 400 600

10 to <14 14 to <15 15 to <20 20 to <25 25 to <32.5 32.5 to <35 35 to <40 ≥ 40

Comparison between FDA and WHO 2010 EFV dosing guidelines

Dose(mg)

Body weight (kg)

[FDA] C12 <1[WHO2010] C12 <1

[FDA] 1<C12<4[WHO2010] 1<C12<4

[FDA] C12 >4[WHO2010] C12 >4 14



0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

13 14 13 11

62 62 6559

25 24 2230

16 14 16 15

59 62 63 64

25 24 21 21

8 11 12 8

5356 60

50

39 33 2842


200 250 250 300 350 400 400 600

10 to <14 14 to <15 15 to <20 20 to <25 25 to <32.5 32.5 to <35 35 to <40 ≥ 40

Dose(mg)

Body weight (kg)

[FDA] C12 <1[WHO2010] C12 <1

[FDA] 1<C12<4[WHO2010] 1<C12<4

[FDA] C12 >4[WHO2010] C12 >4 15




0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

13 14 13 11

62 62 6559

25 24 2230

16 14 16 15

59 62 63 64

25 24 21 21

8 11 12 8

5356 60

50

39 33 2842


200 250 250 300 350 400 400 600

10 to <14 14 to <15 15 to <20 20 to <25 25 to <32.5 32.5 to <35 35 to <40 ≥ 40

Dose(mg)

Body weight (kg)

[FDA] C12 <1[WHO2010] C12 <1

[FDA] 1<C12<4[WHO2010] 1<C12<4

[FDA] C12 >4[WHO2010] C12 >4 16



• 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

Conclusions/Discussion


1) Puthanakit T et al 2009 Antivir Ther. 17


AcknowledgmentsWe 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


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