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

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