clinical pharmacology and formulation challenges of...
TRANSCRIPT
Clinical Pharmacology and Formulation Challenges of Pediatric Antiretroviral
Treatment
Tim R. Cressey
Research AssociatePHPT-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
16th June 2017
18th International Workshop on Clinical Pharmacology of Antiviral Therapy
Chicago, IL, USA
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
• 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
0
100.000
200.000
300.000
400.000
500.000
2000 2003 2006 2009 2012 2015
New HIV infections among children aged 0–14 and adolescents aged 15–19, Global, 2000–2015
Paediatric HIV infections Adolescent HIV infections
http://www.unaids.org/en/resources/presscentre/pressreleaseandstatementarchive/2016/june/20160607_Thailand
June 7, 2016
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E11/Step4/E11_Guideline.pdfhttp://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm425885.pdfZisowsky et al Pharmaceutics 2010, 2, 364-388
Age Classification of Pediatric Patients
Where do we draw the lines for FDA approved doses?
ABC3 Months
28 days
FDA Approval
Birth 2 years 12 years 18 years
DDI2 weeks
FTCBirth
3TC3 Months
TDF2 Years
d4TBirth
ZDV4 weeksPMTCT
Source: Drug Package Inserts
Term Newborns Infants Children Adolescents
EFV3 Months & >3.5 Kg
28 daysBirth 2 years 12 years 18 years
ETV6 years
NVP≥15 days
RPV12 years
Source: Drug Package Inserts
Where do we draw the lines for FDA approved doses?FDA Approval
Term Newborns Infants Children Adolescents
Under Study (IMPAACT P1090 ≥2 months)
ATV3 Months & >5 kg
28 daysBirth 2 years 12 years 18 years
DRV3 years & >10 kg
fAPV4 weeks
LPV/r14 days
NFV2years
TPV2 years
Source: Drug Package Inserts
Where do we draw the lines for FDA approved doses?FDA Approval
Term Newborns Infants Children Adolescents
RAL4 weeks & >3 Kg
28 daysBirth 2 years 12 years 18 years
DTG*>30 kg
EVG18 years
T206 years
MVC2 years & ≥10 kg
GEN12 years & >35 Kg(TAF/FTC/EVG/c)
STB18 years(TDF/FTC/EVG/c)
Where do we draw the lines for FDA approved doses?FDA Approval
Term Newborns Infants Children Adolescents
Source: Drug Package Inserts
Under Study (IMPAACT P1093 ≥4 Weeks)
*EMA: >15kg, 6 to <12 years old (10 mg, 25 mg tablets)
Under Study (IMPAACT 2007)
IMPAACT P1110
DHHS ARV Guidelines for Adults and Adolescents
Last Update July 2016
DHHS ARV Guidelines for Pediatric HIV Infection
Last Update March 2016
1 y
ear
of
age
Major Attempts to Encourage Pediatric Studies
US Food and Drug Administration• 1998 - Pediatirc Rule
• 2002 - The Best Pharmaceutical for Children Act (BPCA)‒ FDA Written Request; Financial Incentives for companies, 6month extension of exclusivity
• 2003 - Pediatric Research Equity Act (PREA)‒ FDA requires companies to perform pediatric studies (could defer/waiver)
• 2007 - 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)
• 2012 - Food and Drug Administration Safety and Information Act (FDASIA)
European Medicines Agency• 2000 – Guideline ICH E11
• 2007 - Paediatric Investigation Plans (PIP)• Agreed in advance by Paediatric Committee (PDCO)
Year
2001
Tenofovir Disoproxil Furmate: Approvals
FDA Approval
2012
2010BPCA and PREA labeling changes
Outstanding PREA PMR:birth to < 2 years of age
Pediatric Exclusivity Granted: September 6, 2011
28 daysBirth 2 years 12 years 18 years28 days
FDA Approval
Birth 2 years 12 years 18 years
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]
WHO Guidelines 2016
2016 WHO – Weight-based Dosing Tables
Prioritization of formulations to be Developed
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
Approaches to Pediatric Studies
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm425885.pdf
Example of Study Design for Dose Finding Studies in Children
IMPAACT P1093 : a phase I/II pharmacokinetic/safety trial of Dolutegravir in Children
STRATIFICATION
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
Cohort V: Infants > 4 weeks to < 6 months
PK Results: DTG 6-12 yrs old
Approval >30 kg by US FDA June 2016
Viani et al. PIDJ 2015; Wiznia al CROI 2016; Ruel et al CROI 2017
Enrollment is a Sequential “Step-down” Approach with Age Cohorts
Pass PK
Pass PK
Pass PK
• Process of sequential enrollment of age groups ---> may lead to delay in drug availability• Can we have alternative designs to speed up data collection?
Absorption• Physiological changes in the gastrointestinal tract can impact the rate and extent of
absorption of oral drugs
Lu et al 2014; JJPT, 19, 4; 262-276Kearns et al 2003; NEJM, 349;12,1157-1167 262-276 Fernandez et al 2011; Pharmaceutics, 3;53-72
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
Needs an understanding of developmental pharmacokinetics
Pediatric Dose Selection
Pediatric Dose SelectionPediatric 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/m2)‒ 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);1077-1097
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: 𝑪𝑳𝑪𝒉𝒊𝒍𝒅= 𝑪𝑳𝑨𝒅𝒖𝒍𝒕 𝒙𝑾𝑻𝑪𝒉𝒊𝒍𝒅
𝑾𝑻𝑨𝒅𝒖𝒍𝒕
𝟎.𝟕𝟓
Anderson et al Annu. Rev. Pharmacol. Toxicol 2008, 48;303-32
Dose per kg is higher in children based on allometric theory
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 =𝑷𝑴𝑨𝑯𝒊𝒍𝒍
𝑷𝑴𝑨𝑯𝒊𝒍𝒍+𝑻𝑴𝟓𝟎𝑯𝒊𝒍𝒍
Anderson et al Arch Dis Child 2013, 98;737-744
GlucuronideConjugation
CYP3A4Metabolized
Prediction of CL with Size + Maturation
• CL in neonates, young infant can be predicted by combining allometric and maturation models:
CL = CLstd x Asize x Bmat
Anderson et al Arch Dis Child 2013, 98;737-744
𝑾𝑻𝑪𝒉𝒊𝒍𝒅𝑾𝑻𝑨𝒅𝒖𝒍𝒕
𝟎.𝟕𝟓 𝑷𝑴𝑨𝑯𝒊𝒍𝒍
𝑷𝑴𝑨𝑯𝒊𝒍𝒍 + 𝑻𝑴𝟓𝟎𝑯𝒊𝒍𝒍
Predictions of CL are close to size-scaled 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
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
𝑷𝑴𝑨𝑯𝒊𝒍𝒍
𝑷𝑴𝑨𝑯𝒊𝒍𝒍 + 𝑻𝑴𝟓𝟎𝑯𝒊𝒍𝒍
𝑾𝑻𝑪𝒉𝒊𝒍𝒅
𝑾𝑻𝑨𝒅𝒖𝒍𝒕
𝟎.𝟕𝟓x (𝑭𝒓𝒂𝒄𝒃𝒊𝒓𝒕𝒉 + (1-𝑭𝒓𝒂𝒄𝒃𝒊𝒓𝒕𝒉) x𝑭𝒓𝒂𝒄𝒊 =
Foissac et al et al JCP 2015, 55(7);739-747
6 y
ears
2 y
ears
6 m
on
ths
SIZE Maturation
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
Maharaj et al 2013 AAPS, 15:2
PBPK Workflow
Khalil et al 2014 AAPS, 16:2
Prophylaxis ------> Treatment
Prophylaxis Treatment
‘Washout’ PK Studies
De
live
ry
Pregnancy
Antiretroviral Prophylaxis
RALCross-placenta
RAL
RAL
Use PK information to
design raltegravir
Dose for newborns
RAL ‘Washout’
Clarke et.al. JAIDS 2014;67:310-315
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 2nd 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; AUC12 6-20 (BID); 12-40 mg.h/L (QD)
Clarke et al. HIV-HEP PK Workshop 2016
This daily RAL regimen was well tolerated during the first 6 weeks of life
8-fold change
Pediatric ARV Formulations
Year2000
Soft Gel-Capsules: 133.3/33.3mgOral Solution: 80/20 mg
(taken with food + refrigeration)
2005
Metrex-Tablets: 200/50mg
(no food restriction or refrigeration)
2007
Metrex-Tablets: Pediatric 100/25mg
(no food restriction or refrigeration)
Lopinavir/Ritonavir: Approvals
Oral Pellets: 40/10 mg(no food restriction or
refrigeration)
2015
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
LPV/r Minitabs (40 mg/10 mg) - CHAPAS 2Phase 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
Year2000
Soft Gel-Capsules: 133.3/33.3mgOral Solution: 80/20 mg
(taken with food + refrigeration)
2005
Metrex-Tablets: 200/50mg
(no food restriction or refrigeration)
2007
Metrex-Tablets: Pediatric 100/25mg
(no food restriction or refrigeration)
Oral Pellets: 40/10 mg(no food restriction or
refrigeration)
2015
Lopinavir/Ritonavir: Approvals
20xx
“4 in 1” FDC Taste-Masked
Granule
AZT or ABC
LPV/r 3TC
ABC/3TC/LPVr
«4-in-1» FDC
“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)
• Phase I PK study planned in Uganda Q4 2017
In vitro, in silico and in vivo preclinical selection of lead SDN formulations
Introduction: preclinical SDN selection
Bulk SDN
Physiologically-based PK simulation
Physiologically-based PK simulation
Dispersal of drugs into water may have explicit benefits for paediatric
formulation without the need for organic solvents.
Owen et al CROR 2017
• ABC/3TC/EFV Scored dispersible table: FDC ratio?
• Data pooled from clinical trials for population pharmacokinetic analyses
(iii) 200/100/200(ii) 120/60/120(i) 150/75/150
• ABC/3TC/EFV FDC strength of 150/75/150 mg for children weighing 10–35 kg
Bouazza et al. JAC; 2016
Antiretrovirals: FDC Across Age Groups
28 days
FDA Approval
Birth 2 years 12 years 18 years
FDC10 kg(ABC/3TC/EFV)
FDC4 kg
(ABC/3TC/LPV/r)4-in-1 ATR12 years & >40 Kg(TDF/FTC/EFV)
COM12 years & >35 Kg
ODE12 years & >35 Kg
(TDF/FTC/RPV)
(TAF/FTC/RPV)
DES12 years & >35 Kg(TAF/FTC)
EPZ25 Kg(ABC/3TC)
EVO18 years(ATV/cobi)
EVO18 years(DRV/cobi)
Generic 60/30 mg
Formulations…..
Source: Drug Package Inserts
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
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
Acknowledgements
38