Commissione del Farmaco dell'Area Vasta Emilia Nord Modena 20 giugno 2011 Alla c.a. Componenti della Commissione del farmaco dell'Area Vasta Emilia Nord Loro Sedi OGGETTO: Verbale riunione 24/05/2011 della Commissione del Farmaco dell'Area Vasta Emilia Nord Presenti: Claudio Andreoli, Angelo Benedetti, Lina Bianconi, Giovanni Bologna, Corrado Busani, Giovanni Maria Centenaro, Giorgio Cioni, Carlo Coscelli, Mauro De Rosa, Roberto Esposito, Anna Maria Gazzola, Sergio Maccari, Anna Maria Marata, Mauro Miselli, Carlo Missorini, Enrico Montanari, Alessandro Navazio, Giovanni Pinelli, Italo Portioli, Daniela Riccò, Nilla Viani. Assenti: Diego Ardissino, Maria Barbagallo, Carlo Cagnoni, Fabio Caliumi, Marilena Castellana, Luigi Cavanna, Silvia Chiesa, Giuseppe Longo, Nicola Magrini, Giovanni Pedretti, Nilla Poncemmi, Saverio Santachiara.
Microsoft powerpoint - #878 croi arrow pk 2010-02-10 finalD.M. Burger PharmD, PhD 864, Department of Clinical Pharmacy Radboud University Nijmegen Medical Tel: +31-24-3616408 Sabrina Bakeera-Kitakaa a , Eva Natukundab a , Lindsay Kendallc l , Quirine Fillekesd s , Addy Kekitiinwaa a , Constance Tumusiimeb e , Peter Mugyenyib i , Ann Sarah Walkerc b , David Burgerd Fax: +31-24-3668755 POSTER NO. 878
Paediatric Infectious Diseases Centre, Mulago, Uganda; b Joint Clinical Research Centre, Kampala, Uganda; c MRC Clinical Trials Unit, London, United Kingdom; d Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands RESULTS - DEMOGRAPHICS RESULTS – PHARMACOKINETICS - 2 Background: Efavirenz (EFV) is commonly used in children over 3 years worldwide, but there is only limited pharmacokinetic (PK) information
Table 1: Baseline demographics of children in substudy of the ARROW trial • In table 2, pharmacokinetic parameters are compared with data from literature2 available in African children.
Methods: 41 HIV-infected Ugandan children aged 3-12 years on generic EFV plus 3TC+ABC were enrolled in a cross-over PK study of twice to once
Table 2: Pharmacokinetic parameters of EFV daily 3TC+ABC 36 weeks after ART initiation in the ARROW trial. Once-daily EFV doses following WHO weight-bands were 200/250/300*/350* mg for children weighing 10-15/15-20/20-25/25-30kg resp., using EFV capsules or *halved 600mg tablets. Intensive plasma PK sampling N wit h 1 or m or e evaluable PK* Li t. data adul ts2 (t=0,1,2,4,6,8,12h post observed ingestion) was performed on twice-daily ART at steady state (PK1) and repeated 4 weeks later (PK2, including a further 24h sample). EFV daily area under the curve (AUC ) and clearance (CL/kg) were estimated using WinNonlin. Predictors of log AUC and CL were assessed using multivariate mixed models, fitting random effects for each child. Results: 39&37 children had evaluable EFV profiles at PK1&PK2 respectively. 16/39(41%) children were boys, 18 were aged 3-6 years and 21 7-12
wei ght -band 10-15 kg, n (%) years. 5/16/15/3 were in the 10-15/15-20/20-25/25-30kg weight-bands. The geometric mean (%CV) AUC was 50.4 (91.7%) and 54.0 (80.8%) AUC0-24 (mg/ L.h) 50.40 [39.12-64.93] 54.00 [42.63-68.39] h.mg/L at PK1 and PK2 respectively, with no significant variation across weight-bands (p=0.51). Between- and within- child %CV were 81% and 28% wei ght -band 15-20 kg, n (%) respectively. 3 sub-populations were identified from normal mixture modeling: 40% children with geometric mean AUC 27.2 h.mg/L, 32% with 49.9 wei ght -band 20-25 kg, n (%) h.mg/L, and 28% with 137 h.mg/L. 6 children at PK1 and 7 at PK2 had sub-therapeutic C8h and/or C12h (<1.0 mg/L); 7/39(18%) at either visit. At wei ght -band 25-30 kg, n (%) PK2, 14/37(38%) children had C24h <1.0 mg/L (median(IQR) [range] 1.1 (0.7-2.5) [0.3-18.4] mg/L). 9 children at PK1 and 10 at PK2 had C8h and/or Values are geometric mean [95% CI] (arithmetic mean [SD] for adult data). Target AUC >49-51 mg/L2,6.
C12h and/or C24h >4.0 mg/L; 11/39(28%) at either visit. Overall mean(SD) clearance was 6.8(3.9) and 6.2(3.7) L/h at PK1 and PK2 respectively and AUC were lower than those previously reported in adults (p=0.04). CL increased by 0.50L/h for every year older (p=0.05), but did not depend on weight (p=0.30), weight-for-age (p=0.56) or height-for-age • There were no differences across weight-bands Conclusion: African children aged 3-12 years, on daily EFV using WHO weight-bands, had lower and highly variable EFV PK parameters compared
7-12 year s, n (%) to data from adults. There were no differences across weight-bands, suggesting no major effect of some using half tablets. Increased EFV doses for children should be investigated, but risk increasing the proportion of children with toxic levels further.
Weight -f or -age, z-score -1.41 (-2.12 t o -0.65) RESULTS - PREDICTORS Keywords: efavirenz, pharmacokinetics, HIV-1, children, Uganda Height -for -age, z scor e -1.80 (-2.80 t o -1.11) Values are n (%) for categorical variables and median (interquartile range, IQR) for continuous variables * Two children were excluded from all analyses, because they increased weight band. Two children were excluded from analysis for • Three sub-populations were identified from normal mixture modeling: 40% children with PK2, because of non-evaluable PK results.
geometric mean AUC 27.2 h.mg/L, 32% with 49.9 h.mg/L, and 28% with 137 h.mg/L. Genetic polymorphisms may play a role.
WHO guidelines for the treatment of HIV-1 infected children >3 yrs recommend an NNRTI RESULTS – PHARMACOKINETICS - 1 • CL/F increased by 0.50 L/h for every year older (p=0.05) (EFV/NVP) or PI plus nucleoside reverse transcriptase inhibitor combination therapy for first line • After adjusting for age, clearance did not depend on weight (p=0.85), weight-for-age (p=0.52) • Mean EFV levels (mg/L) are plotted by PK day in figure 1.
or height-for-age (p=0.80) Until now only little is known about the steady state pharmacokinetics of efavirenz in African Figure 1: mean EFV levels at week 36 (PK1) and week 40 (PK2) A large inter- and intra- subject In this study we determined whether WHO recommended weight-band dosing results in optimal variability was found in EFV PK exposure in the target population • EFV exposure was lower than previously reported in adults parameters (eg 81% and 28% for • A large inter- and intra- subject variability was found in EFV PK parameters • There were no differences across weight-bands, which suggests no major effect of using half - 15% (6/39) children at PK1, 19% (7/37) children at PK2 (7 children in 41 HIV-infected Ugandan children aged 3-12 years on generic EFV plus 3TC+ABC were included in • No predictors were found for AUC and CL/F, but CL/F increased with age the substudy of the ARROW trial (www.arrowtrial.org) total) had a subtherapeutic C • Further analysis of the relationship between EFV concentrations and toxicity is ongoing: viral Children received once daily EFV dosed according to WHO recommendations1 (Table 1) as 50mg or level (<1.0 mg/L). 200mg capsules or halved 600mg tablets loads will also be assayed retrospectively in these children - 38% (14/37) had a subtherapeutic At week 32, children were changed to AM intake of EFV if they were taking EFV PM • Increasing the EFV dose for children should be investigated, and has been proposed by At week 36 after starting EFV + twice daily NRTI regimen a 12 hour PK sampling session was done. WHO. However, higher proportions of children with toxic levels might be expected Samples were taken at t = 0, 1, 2, 4, 6, 8 and 12 hours after observed intake of ART. After PK day - 23% (9/39) children at PK1 and 27% 1. World Health Organisation. Antiretroviral therapy of HIV infection in infants and children: towards universal access: Recommendations for a public health approach
children switched to completely once daily regimen (10/37) children at PK2 (11 children [http://www.who.int/hiv/pub/guidelines/paediatric020907.pdf] 2. Hirt et al; Is the recommended dose of efavirenz optimal in young West African human immunodeficiency
At week 40 intensive plasma PK sampling was repeated and an extra PK sample was drawn at 24 virus-infected children? AAC 2009;53(10): 4407-13. 3. Ren Y, et al; High prevalence of subtherapeutic plasma concentrations of efavirenz in children. JAIDS 2007;45:133–
in total) had a toxic C 136. 4. EMEA, Stocrin, Summary of Product Characteristics. 5. Marzolini et al; Efavirenz plasma levels can predict treatment failure and central nervous system side effects
hours after observed intake in HIV-1-infected patients. AIDS 2001;15:71-75. 6. Fletcher et al; Pharmacokinetics and pharmaco-dynamics of efavirenz and nelfinavir in HIV-infected children participating
level (>4.0 mg/L5) in an area-under-the-curve controlled trial. Clin. Pharmacol. Ther. 2008;83:300–6.
We thank all the patients and staff from all the centres participating in the ARROW trial.
Joint Clinical Research Centre, Kampala, Uganda: P Mugyenyi, V Musiime, VD Afayo, E Bagurukira, J Bwomezi, J Byaruhanga, P Erimu, C Karungi, H Kizito, M Mutumba, WS Namala, J Namusanje, R Nandugwa, TK Najjuko, E Natukunda, M Ndigendawani, SO Nsiyona, F Odongo, K Robinah, M Ssenyonga, D Sseremba, J Tezikyabbiri, CS Tumusiime; MRC/UVRI Uganda Research Unit on AIDS, Entebbe, Uganda: P Munderi, P Nahirya-Ntege, M Aber, FN Kaggwa, P Kaleebu,R Katuramu, JH Kyalimpa, J Lutaakome, L Matama, M Musinguzi, G Nabulime, A Ruberantwari, R Sebukyu, IM Ssekamatte, G Tushabe, D Wangi. Baylor-Uganda, Paediatric Infectious Disease Centre, Mulago Hospital, Uganda: A Kekitiinwa, P Musoke, S Bakeera-Kitaka, R Namuddu, P Kasirye, JK Balungi, A Babirye, J Asello, S Nakalanzi, NC Ssemambo, J Nakafeero, JN Kairu, EK George, G Musoba, J Ssanyu, S Ssenyonjo. University of Zimbabwe, Harare, Zimbabwe: KJ Nathoo, MF Bwakura-Dangarembizi, F Mapinge, T Mhute, T Vhembo, R Mandidewa, D Nyoni, C Katanda, GC Tinago, J Bhiri, D Muchabaiwa, S Mudzingwa, MM Chipiti, M Phiri, J Steamer, CC Marozva, SJ Maturure, L Matanhike, S Tsikirayi, L Munetsi. Medical Research Council Clinical Trials Unit, London, UK: DM Gibb, MJ Thomason, AD Cook, JM Crawley, AA Ferrier, B Naidoo,MJ Spyer, AS Walker, LK Kendall. Independent DART Trial Monitors: R Nanfuka. Trial Steering Committee: I Weller (Chair), E Luyirika, H Lyall, E Malianga, C Mwansambo, M Nyathi, A Wapakhabulo, DM Gibb, A Kekitiinwa, P Mugyenyi, P Munderi, KJ Nathoo: Observers S Kinn, M MacNeil, M Roberts, W Snowden. Data and Safety Monitoring Committee: A Breckenridge (Chair), C Giaquinto, C Hill, J Matenga, J Tumwine. Endpoint Review Committee: G Tudor-Williams (Chair), H Barigye, HA Mujuru, G Ndeezi. Funding: ARROW is funded by the UK Medical Research Council and the UK Department for International Development (DfID). Drugs are provided by GlaxoSmithKline.
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