HIV Reports
Pharmacokinetics of Atazanavir/Ritonavir Among HIV-infected Thai Children Concomitantly Taking Tenofovir Disoproxil Fumarate Torsak Bunupuradah, MD,* Chonnamet Techasaensiri, MD,† Siriwan Keadpudsa, MS,* Narukjaporn Thammajaruk, MPharm,* Amornrat Srimuan, RN,* Thaintip Sahakijpicharn, RN,† Wasana Prasitsuebsai, MD,* Jintanat Ananworanich, MD, PhD,*‡§ and Thanyawee Puthanakit, MD,*¶ on behalf of the HIV-NAT 146 Study Team Background: Atazanavir/ritonavir (ATV/r) is a recommended once-daily protease inhibitor. Tenofovir disoproxil fumarate (TDF) can reduce ATV exposure. The authors studied ATV pharmacokinetic (PK) parameters among children who received atazanavir/ritonavir co-administered with TDF. Methods: HIV-infected children aged 6–18 years with a body weight of 25– 50 kg were eligible. Branded ATV 200 mg/capsule was taken with generic ritonavir 100 mg/tablet once daily plus TDF and lamivudine. A 24-hour PK study was performed at week 4 at t = 0 (pre-dose), 2, 4, 6, 8, 10, 12 and 24 hours. PK parameters were calculated using non-compartmental methods with WinNonlin software. Targeted ATV AUC0–24 was 15 mg h/L and Ctrough was 0.15 mg/L. Comparisons of geometric means of ATV PK parameters between different weight bands were made using regression models. Results: Eighteen HIV-infected children with a median (IQR) age of 13 (11–14) years were enrolled. Median (range) body weight and body surface area were 35 (25–42) kg and 1.21 (0.96–1.35) m2, respectively. Median (IQR) CD4 cell count was 735 (540–1233) cells/mm3. Median (range) of ATV was 164 (145–209) mg/m2. Geometric mean (SD) ATV AUC0–24 was 35.05 (1.06) mg h/L, and ATV Ctrough was 0.31 (1.13) mg/L. No child had ATV AUC0–24 or Ctrough below target levels. There were no significant differences in PK parameters among weight bands. Conclusion: Atazanavir/ritonavir 200/100 mg dosing provided adequate ATV AUC0–24 when used with TDF in HIV-infected Thai children weighing between 25 and 50 kg. Key Words: atazanavir/ritonavir, pharmacokinetics, Thai HIV-infected children (Pediatr Infect Dis J 2014;33:e316–e319)
The study was presented as an oral abstract at the Asian Congress of Pediatric Infectious Diseases, Sri Lanka, November 28–December 1, 2012. From the *HIV-NAT, the Thai Red Cross AIDS Research Centre; †Division of Infectious Disease, Department of Pediatrics, Ramathibodi Hospital, Mahidol University; ‡SEARCH, the Thai Red Cross AIDS Research Centre; §Department of Internal Medicine, and ¶Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. This study was supported by TREAT Asia/amfAR, The Foundation for AIDS Research, with support from the ViiV Healthcare Paediatric Innovation Seed Fund; the Thai National Health Security Office for antiretrovirals and certain laboratory testing; and The Thai Government Pharmaceutical Organization (GPO) for ritonavir 100 mg tablets. Dr. Puthanakit was funded in part as a Senior Researcher Scholar through the Thai Research Fund (TRF). The content of this publication is solely the responsibility of the authors and does not necessarily represent the official views of any of the institutions mentioned above. All participating sites received institutional review board approval for the study. All authors declare no conflict of interest and that members of their immediate families do not have a financial interest in or arrangement with any commercial organization that may have a direct interest in the subject matter of this article. Address for correspondence: Thanyawee Puthanakit, MD, HIV-NAT, the Thai Red Cross AIDS Research Centre, 104 Ratchadamri Road, Pathumwan, Bangkok 10330, Thailand. E-mail: [email protected] Copyright © 2014 by Lippincott Williams & Wilkins ISSN: 0891-3668/14/3312-e316 DOI: 10.1097/INF.0000000000000469
e316 | www.pidj.com
O
nce-daily antiretroviral therapy is a preferred treatment for HIV-infected individuals to improve the acceptability and adherence to the therapy.1,2 Atazanavir/ritonavir (ATV/r) is one of the preferred protease inhibitor (PI) options according to current HIV treatment guidelines.3–5 ATV/r was approved as a oncedaily PI in HIV-infected children older than 6 years of age. The US Food and Drug Adminstration-recommended doses by weight band are 200/100 mg for 25–32 kg, 250/100 mg for 32–39 kg and 300/100 mg for over 39 kg.5,6 There are 4 formulations of ATV: 100, 150, 200 and 300 mg capsules.6 However, ATV 100 mg is currently not available in the USA, and only 200 and 300 mg capsules of ATV are available in Thailand. Tenofovir disoproxil fumarate (TDF) is a once-daily nucleotide reverse transcriptase inhibitor approved for use in children >2 years of age.7 A combination of ATV/r plus TDF has been shown to be effective.8,9 However, TDF can reduce ATV exposure by 25%.10 Several studies of the pharmacokinetics (PK) of boosted PIs in Thai HIV-infected adults and children have shown that Thais have higher PI levels11–15 compared with Caucasians. Avihingsanon et al15 reported an adequate minimum concentration (Ctrough) of ATV (target Cmin ≥ 0.15 mg/L) in 22 Thai adults who received ATV/r 200/100 mg, and levels were comparable to those in Caucasians who received the standard dose of ATV/r (300/100 mg). However, there are limited data on ATV/r PKs in HIV-infected children and adolescents, especially when used with TDF.16,17 Here, the authors report a study to determine ATV PK parameters among children who received reduced doses of ATV in combination with TDF, and compared their results with published data in young adults who received ATV/r 300/100 mg plus TDF.16
MATERIALS AND METHODS From September to December 2012, HIV-infected children aged 6–18 years with a body weight of 25–50 kg, alanine transferase (ALT)
Pharmacokinetics of Atazanavir/Ritonavir Among HIV-infected Thai Children Concomitantly Taking Tenofovir Disoproxil Fumarate Torsak Bunupuradah, MD,* Chonnamet Techasaensiri, MD,† Siriwan Keadpudsa, MS,* Narukjaporn Thammajaruk, MPharm,* Amornrat Srimuan, RN,* Thaintip Sahakijpicharn, RN,† Wasana Prasitsuebsai, MD,* Jintanat Ananworanich, MD, PhD,*‡§ and Thanyawee Puthanakit, MD,*¶ on behalf of the HIV-NAT 146 Study Team Background: Atazanavir/ritonavir (ATV/r) is a recommended once-daily protease inhibitor. Tenofovir disoproxil fumarate (TDF) can reduce ATV exposure. The authors studied ATV pharmacokinetic (PK) parameters among children who received atazanavir/ritonavir co-administered with TDF. Methods: HIV-infected children aged 6–18 years with a body weight of 25– 50 kg were eligible. Branded ATV 200 mg/capsule was taken with generic ritonavir 100 mg/tablet once daily plus TDF and lamivudine. A 24-hour PK study was performed at week 4 at t = 0 (pre-dose), 2, 4, 6, 8, 10, 12 and 24 hours. PK parameters were calculated using non-compartmental methods with WinNonlin software. Targeted ATV AUC0–24 was 15 mg h/L and Ctrough was 0.15 mg/L. Comparisons of geometric means of ATV PK parameters between different weight bands were made using regression models. Results: Eighteen HIV-infected children with a median (IQR) age of 13 (11–14) years were enrolled. Median (range) body weight and body surface area were 35 (25–42) kg and 1.21 (0.96–1.35) m2, respectively. Median (IQR) CD4 cell count was 735 (540–1233) cells/mm3. Median (range) of ATV was 164 (145–209) mg/m2. Geometric mean (SD) ATV AUC0–24 was 35.05 (1.06) mg h/L, and ATV Ctrough was 0.31 (1.13) mg/L. No child had ATV AUC0–24 or Ctrough below target levels. There were no significant differences in PK parameters among weight bands. Conclusion: Atazanavir/ritonavir 200/100 mg dosing provided adequate ATV AUC0–24 when used with TDF in HIV-infected Thai children weighing between 25 and 50 kg. Key Words: atazanavir/ritonavir, pharmacokinetics, Thai HIV-infected children (Pediatr Infect Dis J 2014;33:e316–e319)
The study was presented as an oral abstract at the Asian Congress of Pediatric Infectious Diseases, Sri Lanka, November 28–December 1, 2012. From the *HIV-NAT, the Thai Red Cross AIDS Research Centre; †Division of Infectious Disease, Department of Pediatrics, Ramathibodi Hospital, Mahidol University; ‡SEARCH, the Thai Red Cross AIDS Research Centre; §Department of Internal Medicine, and ¶Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. This study was supported by TREAT Asia/amfAR, The Foundation for AIDS Research, with support from the ViiV Healthcare Paediatric Innovation Seed Fund; the Thai National Health Security Office for antiretrovirals and certain laboratory testing; and The Thai Government Pharmaceutical Organization (GPO) for ritonavir 100 mg tablets. Dr. Puthanakit was funded in part as a Senior Researcher Scholar through the Thai Research Fund (TRF). The content of this publication is solely the responsibility of the authors and does not necessarily represent the official views of any of the institutions mentioned above. All participating sites received institutional review board approval for the study. All authors declare no conflict of interest and that members of their immediate families do not have a financial interest in or arrangement with any commercial organization that may have a direct interest in the subject matter of this article. Address for correspondence: Thanyawee Puthanakit, MD, HIV-NAT, the Thai Red Cross AIDS Research Centre, 104 Ratchadamri Road, Pathumwan, Bangkok 10330, Thailand. E-mail: [email protected] Copyright © 2014 by Lippincott Williams & Wilkins ISSN: 0891-3668/14/3312-e316 DOI: 10.1097/INF.0000000000000469
e316 | www.pidj.com
O
nce-daily antiretroviral therapy is a preferred treatment for HIV-infected individuals to improve the acceptability and adherence to the therapy.1,2 Atazanavir/ritonavir (ATV/r) is one of the preferred protease inhibitor (PI) options according to current HIV treatment guidelines.3–5 ATV/r was approved as a oncedaily PI in HIV-infected children older than 6 years of age. The US Food and Drug Adminstration-recommended doses by weight band are 200/100 mg for 25–32 kg, 250/100 mg for 32–39 kg and 300/100 mg for over 39 kg.5,6 There are 4 formulations of ATV: 100, 150, 200 and 300 mg capsules.6 However, ATV 100 mg is currently not available in the USA, and only 200 and 300 mg capsules of ATV are available in Thailand. Tenofovir disoproxil fumarate (TDF) is a once-daily nucleotide reverse transcriptase inhibitor approved for use in children >2 years of age.7 A combination of ATV/r plus TDF has been shown to be effective.8,9 However, TDF can reduce ATV exposure by 25%.10 Several studies of the pharmacokinetics (PK) of boosted PIs in Thai HIV-infected adults and children have shown that Thais have higher PI levels11–15 compared with Caucasians. Avihingsanon et al15 reported an adequate minimum concentration (Ctrough) of ATV (target Cmin ≥ 0.15 mg/L) in 22 Thai adults who received ATV/r 200/100 mg, and levels were comparable to those in Caucasians who received the standard dose of ATV/r (300/100 mg). However, there are limited data on ATV/r PKs in HIV-infected children and adolescents, especially when used with TDF.16,17 Here, the authors report a study to determine ATV PK parameters among children who received reduced doses of ATV in combination with TDF, and compared their results with published data in young adults who received ATV/r 300/100 mg plus TDF.16
MATERIALS AND METHODS From September to December 2012, HIV-infected children aged 6–18 years with a body weight of 25–50 kg, alanine transferase (ALT)
