Clinical Pharmacology and Formulation Challenges of Pediatric Antiretroviral Treatment

Transcription

1 Clinical Pharmacology and Formulation Challenges of Pediatric Antiretroviral Treatment Tim R. Cressey Research Associate PHPT-IRD UMI 174, Faculty of Associated Medical Sciences, Chiang Mai University, Thailand Department of Molecular & Clinical Pharmacology, University of Liverpool, UK Harvard T.H. Chan School of Public Health, Boston, USA 16 th June th International Workshop on Clinical Pharmacology of Antiviral Therapy Chicago, IL, USA

2 Global Status of Pediatric HIV (<15 yrs old, 2015) 1.8 million children living with HIV (~5% of all people living with HIV ) 150,000 children became newly infected with HIV (7% of new HIV infections) 400 children became newly infected with HIV every day 110,000 children died of AIDS-related illnesses 290 children died of AIDS-related illnesses every day ONLY: 49% of children living with HIV accessed antiretroviral therapy

3 New HIV infections among children aged 0 14 and adolescents aged 15 19, Global, Paediatric HIV infections Adolescent HIV infections Since 2009, new infections among children 0-14 have reduced by nearly 60%, while during the same period adolescents (15-19) only saw a 8% reduction in new infections

4 June 7,

5 Age Classification of Pediatric Patients Zisowsky et al Pharmaceutics 2010, 2,

6 Where do we draw the lines for FDA approved doses? Term Newborns Infants Children Adolescents FDA Approval 2 weeks 3 Months ABC DDI Birth Birth 3 Months 2 Years FTC 3TC d4t TDF PMTCT 4 weeks Birth 28 days 2 years 12 years 18 years ZDV Source: Drug Package Inserts

7 Where do we draw the lines for FDA approved doses? Term Newborns Infants Children Adolescents FDA Approval 15 days 3 Months & >3.5 Kg Under Study (IMPAACT P months) 6 years EFV ETV NVP 12 years RPV Birth 28 days 2 years 12 years 18 years Source: Drug Package Inserts

8 Where do we draw the lines for FDA approved doses? Term Newborns Infants Children Adolescents FDA Approval 4 weeks 3 Months & >5 kg 3 years & >10 kg ATV DRV fapv 14 days 2years 2 years LPV/r NFV TPV Birth 28 days 2 years 12 years 18 years Source: Drug Package Inserts

9 Where do we draw the lines for FDA approved doses? Term Newborns Infants Children Adolescents FDA Approval IMPAACT P weeks & >3 Kg Under Study (IMPAACT P Weeks) >30 kg 18 years (TDF/FTC/EVG/c) 18 years (TAF/FTC/EVG/c) 12 years & >35 Kg RAL DTG* EVG STB GEN Under Study (IMPAACT 2007) 2 years & 10 kg 6 years Birth 28 days 2 years 12 years 18 years *EMA: >15kg, 6 to <12 years old (10 mg, 25 mg tablets) MVC T20 Source: Drug Package Inserts

10 DHHS ARV Guidelines for Adults and Adolescents Last Update July 2016

11 1 year of age DHHS ARV Guidelines for Pediatric HIV Infection Last Update March 2016

12 Major Attempts to Encourage Pediatric Studies US Food and Drug Administration Pediatirc Rule The Best Pharmaceutical for Children Act (BPCA) FDA Written Request; Financial Incentives for companies, 6month extension of exclusivity Pediatric Research Equity Act (PREA) FDA requires companies to perform pediatric studies (could defer/waiver) Food and Drug Administration Amendment Acts (FDAAA) Allowed extrapolation of finding from adult studies, or from different pediatirc age groups, accompanied by pharmacokinetic studies Pediatric Review Committee (PeRC) Food and Drug Administration Safety and Information Act (FDASIA) European Medicines Agency 2000 Guideline ICH E Paediatric Investigation Plans (PIP) Agreed in advance by Paediatric Committee (PDCO)

13 Tenofovir Disoproxil Furmate: Approvals Year FDA Approval 2001 BPCA and PREA labeling changes 2010 Pediatric Exclusivity Granted: September 6, Outstanding PREA PMR: birth to < 2 years of age Birth 28 days 2 years 12 years 18 years

14 Involvement of World Health Organization (WHO) WHO strongly encourages the development of formulations appropriate for paediatric use, particularly solid formulations in doses and FDC products that can be used by children <14 kg. Paediatric ARV Working Group Meeting (PAWG) Formed in 2006 to guide development of WHO dosing recommendations WHO-PAWG has recommended simplified ARV dosing based on weight bands for use in resource-limited settings The purpose of weight band dosing is to make standardized ARV treatment practical in resource limited settings by simplifying drug delivery and reducing prescription errors. [Elaine Abrams, Victor Musiime and Tim Cressey - Co-Chairs: 2017]

15 2016 WHO Weight-based Dosing Tables WHO Guidelines 2016

16 Prioritization of formulations to be Developed

17 Approaches to Pediatric Studies PK Only ---> Full extrapolation similar progression of disease similar response of the disease to treatment similar exposure-response or concentration-response relationship drug concentration is measureable and predictive of the clinical response PK + PD Approach ---> Partial extrapolation Inadequate information on exposure-response PK + Efficacy Approach ---> No extrapolation progression of disease unique to pediatric patients progression/response to intervention undefined Age-appropriate Formulations relative bioavailability study comparing formulation to the approved drug in adults. potential drug-food or vehicle interactions should be considered

18 Example of Study Design for Dose Finding Studies in Children IMPAACT P1093 : a phase I/II pharmacokinetic/safety trial of Dolutegravir in Children Enrollment is a Sequential Step-down Approach with Age Cohorts STRATIFICATION PK Results: DTG 6-12 yrs old Cohort I: Adolescents 12 to <18 years Cohort IIA: Children 6 to <12 years Cohort III: Children 2 to < 6 years Cohort IV: Children 6 months to < 2 years Pass PK Pass PK Pass PK Cohort V: Infants > 4 weeks to < 6 months Approval >30 kg by US FDA June 2016 Process of sequential enrollment of age groups ---> may lead to delay in drug availability Can we have alternative designs to speed up data collection? Viani et al. PIDJ 2015; Wiznia al CROI 2016; Ruel et al CROI 2017

19 Pediatric Dose Selection Needs an understanding of developmental pharmacokinetics Absorption Physiological changes in the gastrointestinal tract can impact the rate and extent of absorption of oral drugs Distribution Maturation leads to dramatic changes in relative amount of body water / fat; protein binding reduced in neonates Metabolism Age-dependent development of metabolizing enzymes (Phase I & II) and each enzyme has a unique pattern of development Excretion Renal Function: GRF rapid increase during first weeks of life; then rises steadily reaching adults values by 8-12 months of life Kearns et al 2003; NEJM, 349;12, Fernandez et al 2011; Pharmaceutics, 3;53-72 Lu et al 2014; JJPT, 19, 4;

20 Pediatric Dose Selection Pediatric dose based on fraction of the adult dose which normally involves scaling (normalizing) for size using different approaches: Bodyweight-Based Dosing Regimens (mg/kg) Drug clearance per Kg is larger in children in adults (perhaps due to increased relative liver size and/or hepatic drug flow) Body Surface Area-Based Dosing Regimens (mg/m 2 ) BSA-based dose for a 12 yr child is 1.2x the adult-referenced bodyweight-based Absolute dosage for 2 yr child, adjusted based on BSA, is 1.7 times (70%) higher than the dosage adjusted based on bodyweight Menson et al 2006 BMJ; 332;11; Bartelink et al Clin Pharmacokinet 2006, 45, (1);

21 Alternative ways to consider weight for drug dosing? Drug elimination is non-linearly related to SIZE (i.e. weight) Linear mg/kg scaling --> often underestimation of dose in infants (1-3 yrs) Weight-based Allometric scaling Predicting CL between a child and adult: CL Child = CL Adult x WT Child WT Adult 0.75 Dose per kg is higher in children based on allometric theory Anderson et al Annu. Rev. Pharmacol. Toxicol 2008, 48;303-32

22 What about neonates: need to also consider Maturation Allometric scaling alone is insufficient to describe CL in neonates/infants Dosing regimens for neonates not same as children ----> immature physiology AGE can describe Maturation process (i.e. independent of size) Post-Menstrual Age (PMA): Maturation = PMA Hill PMA Hill +TM 50 Hill CYP3A4 Metabolized Glucuronide Conjugation Anderson et al Arch Dis Child 2013, 98;

23 Prediction of CL with Size + Maturation CL in neonates, young infant can be predicted by combining allometric and maturation models: CL = CL std x A size x B mat WT Child WT Adult 0.75 PMA Hill PMA Hill + TM 50 Hill Predictions of CL are close to sizescaled adult values 2 years of age) Children ( 2 yrs) are small adults PK predictable from adults based Only on WT Neonates are immature children PK predictable based from adults based on WT AND age Anderson et al Arch Dis Child 2013, 98;

24 6 months 2 years 6 years Frac i = WT Child WT Adult 0.75 x SIZE (Frac birth + (1-Frac birth ) x Maturation PMA Hill PMA Hill + TM 50 Hill WT-based allometry WT-age-based model Age-related maturation of CL reached 90% of the adult value within 1.5 years of life For children <2 years old, allometric scaling alone systematically overestimated CL Foissac et al et al JCP 2015, 55(7);

25 Physiologically-based Pharmacokinetics (PBPK) for Pediatirc Dose Selection FDA supports use of PBPK modeling for pediatric drug development PBPK may complement allometry for predicting PK in younger age groups PBPK Workflow Maharaj et al 2013 AAPS, 15:2 Khalil et al 2014 AAPS, 16:2

26 Prophylaxis > Treatment Prophylaxis Treatment

27 Delivery Washout PK Studies RAL Cross-placenta RAL Washout RAL Antiretroviral Prophylaxis RAL Pregnancy Use PK information to design raltegravir Dose for newborns Clarke et.al. JAIDS 2014;67:

28 IMPAACT P1110: RAL less 6 weeks Study population: HIV-1 exposed full-term neonates (aged 48 hours) assessed as high risk of acquiring HIV-1 infection Cohort 1: Oral granules: RAL within 48 hours and 2 nd dose at 7-10 days of life Cohort 2: Oral granules: RAL once daily started within 48 hours until 6 weeks of life PK Targets: Cmin >33 ng/ml; Cmax <8724 ng/ml; AUC (BID); mg.h/l (QD) 8-fold change This daily RAL regimen was well tolerated during the first 6 weeks of life Clarke et al. HIV-HEP PK Workshop 2016

29 Pediatric ARV Formulations

30 Lopinavir/Ritonavir: Approvals Soft Gel-Capsules: 133.3/33.3mg Oral Solution: 80/20 mg (taken with food + refrigeration) Metrex-Tablets: Pediatric 100/25mg (no food restriction or refrigeration) Oral Solution 42.4% alcohol (v/v) 15.3% (w/v) Propylene Glycol Toxic rick for newborns PMA >42 wks, PNA >14 days) Short shelf life Poor taste Year Metrex-Tablets: 200/50mg (no food restriction or refrigeration) Oral Pellets: 40/10 mg (no food restriction or refrigeration)

31 LPV/r Minitabs (40 mg/10 mg) - CHAPAS 2 Phase I, open-label, randomized crossover PK study in Ugandan (n=77): Cohort A (3 to 12 months): LPV minitabs vs. Syrup Innovator (n=19) Cohort B (1 4 yrs): LPV minitabs vs. Syrup Innovator (n=26) Cohort C (4 13 yrs): LPV minitabs vs. tablets (100/25mg, Cipla) (n=32) LPV/r dosed according to WHO 2010 guidelines with food Musiimee al 2014 JIADS

32 Lopinavir/Ritonavir: Approvals Soft Gel-Capsules: 133.3/33.3mg Oral Solution: 80/20 mg (taken with food + refrigeration) Metrex-Tablets: Pediatric 100/25mg (no food restriction or refrigeration) 4 in 1 FDC Taste-Masked Granule Year Metrex-Tablets: 200/50mg (no food restriction or refrigeration) xx Oral Pellets: 40/10 mg (no food restriction or refrigeration)

33 4-in-1 FDC: ABC/3TC/LPV/r 4 ARVs in 1: Granules (FDC) in a capsule Capsule simple to open, Use with water, milk, food Taste-Masked No Cold Chain Suitable for infants < 2 mos-3 yrs (& children who cannot swallow pills) LPV/r AZT or ABC 3TC Phase I PK study planned in Uganda Q ABC/3TC/LPVr «4-in-1» FDC

34 Introduction: preclinical SDN selection Bulk SDN Dispersal of drugs into water may have explicit benefits for paediatric formulation without the need for organic solvents. Physiologically-based PK simulation Physiologically-based PK simulation In vitro, in silico and in vivo preclinical selection of lead SDN formulations Owen et al CROR 2017

35 ABC/3TC/EFV Scored dispersible table: FDC ratio? Data pooled from clinical trials for population pharmacokinetic analyses (i) 150/75/150 (ii) 120/60/120 (iii) 200/100/200 ABC/3TC/EFV FDC strength of 150/75/150 mg for children weighing kg Bouazza et al. JAC; 2016

36 Antiretrovirals: FDC Across Age Groups FDA Approval 4 kg (ABC/3TC/LPV/r) 4-in-1 (ABC/3TC/EFV) 10 kg (TDF/FTC/EFV) (TDF/FTC/RPV) 12 years & >40 Kg 12 years & >35 Kg FDC FDC ATR COM Generic 60/30 mg Formulations.. (TAF/FTC/RPV) 12 years & >35 Kg (TAF/FTC) 12 years & >35 Kg (ABC/3TC) 25 Kg (ATV/cobi) 18 years (DRV/cobi) 18 years Birth 28 days 2 years 12 years 18 years ODE DES EPZ EVO EVO Source: Drug Package Inserts

37 Summary Optimal drug dosing across the pediatirc population needs an understanding of developmental pharmacokinetics The standard approach of deriving pediatric dose based on fraction of the adult dose (i.e. mg/kg) often leads to under dosing in young children In neonates and young infant the CL can be relatively well predicted by combining allometric (i.e. Size --> weight) and maturation models Data on prophylaxis regimens can be used to help predict treatment exposures in young children ---> unify prophylaxis and treatment regimens (without large scale trials) Development of formulations are a major hurdle for pediatirc drug development More FDCs for children on the horizon.long acting.. Novel drug monitoring tools/stratergies to support medication adherence

38 Acknowledgements Pediatric Antiretroviral Working Group Edmund Capparelli Mark Mirochnick Diana Clarke Paolo Denti Carlo Giaquinto Di Gibb Marc Lallemant David Burger Angela Colbers Elaine Abrams Martina Penazzato 38