clinical pharmacology strategy to inform dosing of...

9th International Workshop on HIV & Women; March 2-3, 2019; Seattle, WA

1ViiV Healthcare, Research Triangle Park, NC; 2ViiV Healthcare, Brentford, UK

Clinical Pharmacology Strategy to Inform

Dosing of Antiretroviral Drugs in Women:

Dolutegravir as a Case Study

Kimberly Adkison,1 Romina Quercia,2 Justin Koteff,1 Brian Wynne,1 Katy Moore,1

Jean van Wyk2


Gender Differences in Physiology & Pharmacokinetics

Adkison et al. HIV & Women 2019; Seattle, WA. Oral.

Photo by Unknown Author is licensed under CC BY-ND

Organ Function

• Gastric pH: FM

• Cardiac Output: F


Regulatory Authorities RecommendEnrollment of Women In Clinical Trials



http://www.fda.gov/downloads/Drugs/.../Guida

nces/ucm072133.pdfhttp://www.fda.gov/downloads/RegulatoryInform

ation/Guidances/ucm127505.pdf

http://www.fda.gov/downloads/drugs/guidanc

ecomplianceregulatoryinformation/guidances/

ucm450636.pdf

https://www.fda.gov/downloads/Drugs/Gui

danceComplianceRegulatoryInformation/

Guidances/UCM603873.pdf

Guidance on Characterization of PK and Exposure-Response Relationships in Women


https://www.ema.europa.eu/documents/scientific-

guideline/guideline-clinical-investigation-steroid-

contraceptives-women_en.pdf

https://www.ema.europa.eu/documents/scientific-guideline/guideline-

clinical-investigation-medicinal-products-hormone-replacement-therapy-

oestrogen-deficiency_en.pdf

http://www.fda.gov/downloads/Drugs/.../Guidances/ucm072133.pdfhttp://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm127505.pdfhttp://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm450636.pdfhttps://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM603873.pdfhttps://www.ema.europa.eu/documents/scientific-guideline/guideline-clinical-investigation-steroid-contraceptives-women_en.pdfhttps://www.ema.europa.eu/documents/scientific-guideline/guideline-clinical-investigation-medicinal-products-hormone-replacement-therapy-oestrogen-deficiency_en.pdf


• Initial DTG clinical development program (i.e., 1st DTG single-entity regulatory submission and approval) included:

– 452 female participants (22%) in total across 35 Phase 1-3 studies

– 143 female participants (27%) in 28 Phase 1 studies in healthy subjects

• To inform DTG dose in women, will review DTG clinical pharmacology strategy and timing and types of studies to understand drug PK and PKPD relationships

Inclusion of Women in DTG Clinical Development


NDA/MAA

Phase 1 Phase 3Phase 2 Phase 4


• Initial DTG clinical development program (i.e., 1st DTG single-entity regulatory submission and approval) included:

– 452 female participants (22%) in total across 35 Phase 1-3 studies

– 143 female participants (27%) in 28 Phase 1 studies in healthy subjects

• To inform DTG dose in women, will review DTG clinical pharmacology strategy and timing and types of studies to understand drug PK and PKPD relationships



NDA/MAA


Women of non-

childbearing potential

FTIH • SAD/MAD

• Healthy adults

Abbreviations: FTIH=First time in human; SAD=single ascending dose; MAD=multiple ascending dose; NDA=New Drug Application;

MAA=Medicine Authorisation Application


• Dose-proportional PK supporting once daily dosing

• Data from small number of women suggests PK similar between genders

FTIH: Single and Multiple Ascending Dose Studies

• Placebo-controlled, double blind studies to determine safety, tolerability & PK in

healthy adults

• Single dose (ING111207):– DTG 2, 5, 10, 25, 50, 100mg

– N=10 per cohort (8 active/2 placebo)

– 5 female, 20 male enrolled

• Multiple dose (ING111322):– DTG 10, 25, 50mg once daily x 10 days

– N=10 per cohort (8 active/2 placebo)

– 5 female, 27 male enrolled

Study Design Results


Min S, Song I, Borland J, et al. Pharmacokinetics and safety of

S/GSK1349572, a next-generation HIV integrase inhibitor, in

healthy volunteers. Antimicrob Agents Chemother. 2009;54(1):254-8.

PK Conclusions




Abbreviations: FTIH=First time in human; SAD=single ascending dose


FTIH • SAD/MAD

• Healthy adults

NDA/MAA

Women of non-


PK




Abbreviations: FTIH=First time in human; SAD=single ascending dose; MAD=multiple ascending dose; POC=proof-of-concept; ADME=absorption,

distribution, metabolism, elimination; DDI=drug-drug interaction study.


FTIH • SAD/MAD

• Healthy adults

NDA/MAA

POC• Dose-ranging

monotherapy

• HIV, adults

Women of non-


PK


• Monotherapy associated with potent antiretroviral activity with 2.5 log ↓ in HIV-RNA.

• Antiviral activity increased with increasing dose• Clear exposure-response relationship defined

with C best predictor of antiviral response

• PK in HIV similar to healthy subjects

Proof of Concept:Dose-Ranging Monotherapy in PLHIV


Min S, Sloan L, DeJesus E, Hawkins T, McCurdy L, Song I, Stroder R, Chen S, Underwood M, Fujiwara T, Piscitelli S, Lalezari J. Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of dolutegravir as 10-day monotherapy in HIV-1 infect adults.

• Multicenter, randomized, parallel, double blind, placebo-controlled, dose-ranging study

• DTG 2, 10, 50mg q24 x 10 days• N=10 (8 active/2 placebo) per dose cohort• PK and HIV-RNA measured over 21 days

PK and PKPD Conclusions

Study Design

Results




Abbreviations: FTIH=First time in human; SAD=single ascending dose; MAD=multiple ascending dose; POC=proof-of-concept


FTIH • SAD/MAD

• Healthy adults

NDA/MAA

POC• Dose-ranging

monotherapy

• HIV, adults

Women of non-


PK PKPDPK







FTIH • SAD/MAD

• Healthy adults

NDA/MAA

POC• Dose-ranging

monotherapy

• HIV, adults

Women of non-


Drug-Drug Interactions, ADME, Special Populations• Female genital tract distribution study

• Hormonal contraceptive DDI in healthy women

PK PKPDPK


Female Genital Tract PK & Distribution Study

• N=8 healthy women

• DTG 50mg once daily for 5-7 days• Plasma and cervicovaginal fluid samples over

24h following single and multiple doses.

• Cervical and vaginal tissue biopsies

Study Design

• Under steady-state conditions, DTG in cervicovaginal fluid was 6% of plasma.

• DTG exposure in cervical and vaginal tissue were similar and ~ 10% of plasma.

• Greater accumulation after multiple dosing in tissues compared to plasma.

• DTG concentrations above the protein-adjusted IC90 in 100% of cervical tissue and 88% of

vaginal tissue samples.

Results


Study 115465: Adams JL, Patterson KB, Prince HM, et al. Single and multiple dose pharmacokinetics of dolutegravir in the genital tract of HIV-negative women.

Antivir Ther. 2013;18(8):1005-13..

• DTG distributes into the female genital tract

PK Conclusion

STEADY-STATE


Hormonal Contraceptive Drug-Drug Interaction Study

• 2-period, double-blind, placebo-controlled, crossover study in N=16 healthy women

• Oral norgestimate/ethinyl estradiol (NGM/EE) + DTG 50mg once daily

Study Design Results


1. Study ING111855: Song IH, Borland J, Chen S, Wajima T, Peppercorn AF, Piscitelli SC. Dolutegravir Has No Effect on the Pharmacokinetics of

Oral Contraceptives With Norgestimate and Ethinyl Estradiol. Ann Pharmacother. 2015;49(7):784-9.

• No effect of DTG on PK or PD of hormonal contraceptive components

• NGM/EE can be administered with DTG without dose adjustment, allowing women on hormonal contraceptives to be included in Phase 2b/3.

PK Conclusions







FTIH • SAD/MAD

• Healthy adults

NDA/MAA

POC• Dose-ranging

monotherapy

• HIV, adults

Women of non-




PK PKPDPK

PK







FTIH • SAD/MAD

• Healthy adults

NDA/MAA

POC• Dose-ranging

monotherapy

• HIV, adults

Phase 2b

Dose-ranging

+ other ART•SPRING-1 (naïve)

•VIKING (INSTI-r)

Women of childbearing potential

using contraception (may include

hormonal contraceptives)

Pivotal Safety & Efficacy •Tmt-Naive: SPRING-2, SINGLE

•Tmt-Exp: SAILING

• INSTI-Res: VIKING-3

Women of non-


Population Pharmacokinetic Analyses• Treatment-Naive & Treatment-Experienced



PKPKPDPK

PK


DTG Population PK AnalysisTreatment-naïve from 3 Phase 2/3 trials (POC, SPRING-1, SPRING-2)

• DTG 10 to 50mg alone or + ABC/3TC or TDF/FTC • 82/563 (15%) were femaleTreatment-experienced from 3 Phase 2/3 trials (SAILING, VIKING, VIKING-3

• DTG 50mg QD or 50mg BID in combination with PI/r, NRTIs, NNRTIs• 152/574 (26%) were female

DTG PK in PLHIV + Factors that Influence PK VariabilityNo DTG Dose Adjustment by Intrinsic Factors Necessary


Zhang J, Hayes S, Sadler BM, et al. Population pharmacokinetics of dolutegravir in HIV-infected treatment-naive patients.

Br J Clin Pharmacol. 2015;80(3):502-14.

• Factors that influence PK variability (age, gender, weight, total bilirubin, and smoking status) had a relatively small effect on DTG PK parameters; e.g., females predicted to have 18 to 21% higherbioavailability versus males

• No clinically significant effect on DTG AUC(0-tau), Cmax and Cτbased on PK/PD and Phase 3 subgroup analysis demonstrating no impact on gender (and other factors) on response

• No DTG dose adjustment by these intrinsic factors is necessary

Results

DTG PK described by linear 1-compartment

model w/1st order absorption, absorption

lag time and 1st order elimination


Phase 2b

Dose-Ranging •SPRING-1 (naïve)

•VIKING (INSTI-r)


•Tmt-Exp: SAILING







FTIH • SAD/MAD

• Healthy adults

NDA/MAA

POC• Dose-ranging

monotherapy

• HIV, adults


using contraception

(may include hormonal contraceptives)

Women of non-





PK PKPDPK PK PKPD

PK

PK

PK


Phase 2b

Dose-Ranging •SPRING-1 (naïve)

•VIKING (INSTI-r)


•Tmt-Exp: SAILING







FTIH • SAD/MAD

• Healthy adults

NDA/MAA

POC• Dose-ranging

monotherapy

• HIV, adults


using contraception


Women of non-


Post-Approval Trials•ViiV-, collaborative-, and

externally-sponsored studies

•Women, incl pregnant women

(e.g, ARIA, P1026s, PANNA,

DolPHIN-1 ) & contraceptive

implant DDI studies




PK PKPDPK PK PKPD

PK

PK

PK


Pharmacokinetics in Pregnant Women

IMPAACT P1026s1

• N=29 2nd, 3rd trimester & post-partum in Americas

PANNA2

• N=9 3rd trimester & post-partum in Europe

DolPHIN-13

• N=29 3rd trimester & post-partum in Africa

Studies

• DTG PK exposures in the 2nd and 3rd trimesters were comparable to historical

PK data in non-pregnant Phase 3 trial

participants; however, they tended to be

lower than post-partum values.

• PK and virology results suggest that acceptable exposures are achieved in

pregnancy with standard dosing

PK Results


1. Mulligan N, Best B, Wang J, Capparelli E, Stek A, Barr E, Buschur S, Acosta E, Smith E, Chakhtoura N,, Burchett S, Mirochnick M for the IMPAACT P1026s Protocol

Team. Dolutegravir Pharmacokinetics in Pregnant and Postpartum Women Living with HIVAIDS. 2018;32(6):729-727. 2.Bollen P, Colbers A, Schalkwijk S et al. A

Comparison of the Pharmacokinetics of Dolutegravir During Pregnancy and Postpartum. 18th International Workshop on Clinical Pharmacology of Antiviral Therapy. 2017;14-

16 June: Chicago, USA. : http://regist2.virology-education.com/2017/18AntiviralPK/10_Bollen.pdf. 3. Orrell C et al. DolPHIN-1: randomised controlled trial of dolutegravir

(DTG)- versus efavirenz (EFV)-based therapy in mothers initiating antiretroviral treatment in late pregnancy. AIDS 2018. Amsterdam. 23–27 July 2018.

http://regist2.virology-education.com/2017/18AntiviralPK/10_Bollen.pdf



•Tmt-Exp: SAILING


Post-Approval Trials•ViiV-, collaborative-, and

externally-sponsored studies

•Women, incl pregnant women

(e.g, ARIA, P1026s, PANNA,

DolPHIN-1 ) & contraceptive

implant DDI studies

Overview of Clinical Development: Dolutegravir





FTIH • SAD/MAD

• Healthy adults

NDA/MAA

POC• Dose-ranging

monotherapy

• HIV, adults




using contraception


Women of non-



PK PKPD

PK

PK PK

PK

PK

PKPD

Phase 2b

Dose-ranging

+ other ART•SPRING-1 (naïve)

•VIKING (INSTI-r)PK PKPD


The appropriate dose for women, and other

populations, is determined from clinical

pharmacology (e.g., PK, DDI, exposure-

antiviral response and safety relationships)

+ Ph2 to 3 safety and efficacy studies

The Value of Women in DTG Clinical Studies


No DTG dose adjustment for women,Includes women on contraceptives

and during the 2nd & 3rd trimester of pregnancy

Downloaded from Dreamtimes.com


Thank you to the MANY

study participants,

investigators & clinic staff,

and ViiV/GSK staff who

contributed to

dolutegravir’s clinical

development program

Acknowledgments



Thank you

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