dolutegravir pharmacokinetics during pregnancy and...

Dolutegravir pharmacokinetics during pregnancy and postpartumAngela Colbers, PhDRadboud University Medical Center Nijmegen, The Netherlands

Angela Colbers1, Pauline Bollen1, Jolien Freriksen1, Deborah Konopnicki2, Katharina Weizsäcker3, Carmen Hidalgo Tenorio4, José Moltó5, Graham Taylor6, Irene Alba-Alejandre7, Reinout van Crevel1, David Burger1, on behalf of the PANNA network

9th International Workshop on HIV & Women2-3 March 2019, Seattle, USA.

1 Radboud University Medical center, Nijmegen, The Netherlands. 2 Saint-Pierre University Hospital, Brussels, Belgium. 3 Department of Obstetrics, Charité Universitätsmedizin, Berlin, Germany. 4 Hospital Universitario Virgen de las Nieves Granada, Granada, Spain. 5 HIV Unit, Hospital Universitari Germans Trias i Pujol, Badalona, Spain. 6 Imperial College Healthcare NHS Trust, London, UK. 7Department of Obstetrics, Ludwig-Maximilans-University, Munich, Germany.

A European clinical pharmacology network to investigate the Pharmacokinetics of newly developed ANtiretroviral agents in HIV-infected pregNAnt women

www.pannastudy.com

9th International Workshop on HIV & Women2-3 March 2019 in Seattle, USA.

• NEAT/PENTA

• Merck

• BMS

• Janssen

• ViiV Healthcare

• Gilead


Partners PANNA

• 1.5 million women living with HIV deliver per year

• Mother-to-child-transmission (MTCT) of HIV while using antiretroviral medication during pregnancy; 20% to <2% chance

• DTG is a preferred INSTI for treatment of HIV

• DTG was/is a promising ARV to be used in pregnancy


Pregnancy and HIV+

• DTG NTD!!! 0.9% versus 0.1% background when used at conception.

• Tsepamo study, Botswana


Dolutegravir

• DTG is still reported as a preferred INSTI in pregnancy, as long as not taken in the

first trimester

• DHHS: NOT to be used <14 weeks gestational age

• SmPC DTG: NOT to be used in the first trimester (14 weeks)


Dolutegravir

• Pregnant women are excluded from clinical trials in development phase

• After marketing of the new drug, HIV+ women get pregnant using these new drugs

• Knowledge gaps:

1. Placental passage

2. Safety for the unborn child

3. Pharmacokinetics in pregnancy


Pregnancy and HIV+

• Pregnancy may induce changes in PK of ARVs

• In many cases lower plasma concentrations are the result

• Adequate exposure to ARVs is necessary to optimize VL reduction and prevent

resistance

• Low VL is needed to prevent MTCT


Why study pharmacokinetics of ARVs in pregnant women?


Expected changes in pharmacokinetics of ARVs in pregnant women

Total body water

Total body fat

Plasma volume

gastric emptying and intestinal motility

gastric pH

CYP2D6 activity

CYP3A4 activity

Hepatic blood flow

GFR

Albumin conc.

• Limited data is available about the pharmacokinetics of dolutegravir during

pregnancy and the placental passage of dolutegravir

• IMPAACT P1026, Mulligan et al AIDS 2018 (publication)

• DolPHIN-1, poster at CROI 2018 presentation AIDS 2018

• Preliminary data PANNA presented by Bollen in 2017


Dolutegravir

• To describe the pharmacokinetics of dolutegravir in the 3rd trimester of pregnant

HIV-infected women and at post-partum

• To describe the safety of dolutegravir during pregnancy and the efficacy in terms of

viral load response of the mother and prevention of mother to child transmission

• To assess placental passage of dolutegravir


Objectives


Methods

3rd trimester postpartum

~ 33wks GA 4-6 weeks after delivery

PK curve dolutegravir PK curve dolutegravir (reference)

Blood samples: predose, 0.5, 1, 2, 3, 4, 6, 8, 12 and 24h after dosing


Methods

3rd trimester postpartum

~ 33wks GA 4-6 weeks after delivery

PK curve dolutegravir PK curve dolutegravir (reference)

Blood samples: predose, 0.5, 1, 2, 3, 4, 6, 8, 12 and 24h after dosing

Cord blood at delivery

(CB/MB ratio)

• 17 women on dolutegravir 50mg QD included in 7 European hospitals (June 2015 – Sep 2018)

• 50% conceived on DTG

• 10 women had paired curves; 15 evaluable third trimester curves


Subject characteristics

Demographics at delivery Median (range) or n(%)

Age, years 31 (21-42)

Gestational age, weeks 40 (34-42)

Birth weight, grams 3170 (2120-4040), 1 unknown

RegimenDTG + TDF/FTC DTG/ABC/3TCDTG + DRV/r +TDFDTG+DRV/r

7 (41%)8 (47%)1 (6%)1 (6%)


Plasma concentration vs. time curve


Pharmacokinetic parametersPK parameter

Third trimester (n=15)

Postpartum(n=10)

GM Ratio* (%) [90% CI] n=10

AUC0-24h (h*mg/L) 40.8 (35) 47.0 (42) 86 (68-110)

Cmax (mg/L) 3.15 (31) 3.34 (32) 93 (77-113)

Cmax unbound (mg/L) 0.012 (44) 0.009 (63) 134 (93-193)

Fraction unbound (%) 0.36 (0.27-0.46) 0.29 (0.22-0.38) 142 (101-200)

Tmax (h) 3.0 (1.0-4.5) 3.8 (0.5-8.0)

C0h (mg/L) 1.00 (90) 1.22 (105) 79 (48-132)

Ctrough (mg/L) 0.68 (84) 1.03 (68) 71 (49-102)

Cmin (mg/L) 0.66 (90) 0.92 (84) 74 (49-112)

Cmin unbound (mg/L) 0.003 (87) 0.003 (102) 86 (50-148)

Fraction unbound (%) 0.40 (0.28-0.70) 0.34 (0.23-0.70) 120 (84-170)

CL/F (L/h) 1.23 (35) 1.06 (42) 116 (91-147)Geometric means + CV%* Third trimester vs postpartum. Tmax: median (min-max); fraction unbound: median (IQR).


Individual exposure and Ctrough

14% 29%

Orange line represents the minimal therapeutic target concentrationof 0.32 mg/L (Min, 2011)


Cmin total and unbound DTG

Geometric means and individual values

26% 14%

• At third trimester 2 participants had Ctrough below target of 0.32 mg/L (Min et al

2011, in vivo EC90, phase 2 study): 0.11 mg/L and 0.28 mg/L

• One on DTG/ABC/3TC, one on DTG/DRV/rtv (QD)

• Both showed liver enzyme abnormalities

• Both had undetectable VL at third trimester visit


Ctrough below target


IMPAACT p1026s

AIDS 2018, Mulligan et al

AUC 29% Ctrough 34%


DolPHIN-1AUC 5% Ctrough 7%


Results ARVs


CB/MB-ratio

• Approaching delivery all participants had a VL <50 cps/mL.

• One intrauterine fetal death (34 weeks of pregnancy) was reported due to

cholestasis of pregnancy syndrome. One infant had a congenital abnormality:

hypospadia, unlikely related to DTG. No NTDs reported.

• 2 maternal SAEs, not drug related; hospital admissions due to suspected pre-

eclampsia/HELLP-syndrome.

• 14/14 children were HIV un-infected. 3 missing: 1 child died, 2 status unknown (lost

to follow-up).


Safety & efficacy

• Although variability is high, DTG AUC0-24h seems similar in late pregnancy and

postpartum.

• DTG total trough plasma concentrations seem lower in the 3rd trimester compared

to postpartum. However, unbound dolutegravir plasma Cmin are unchanged in the

3rd trimester as compared to postpartum.

• In this study the DTG free fraction in pregnant women in the 3rd trimester seems

higher than postpartum (42% for Cmax and 20% for Cmin).

• These findings, coupled with the undetectable viral loads at delivery, suggest

uncompromised efficacy of dolutegravir 50mg QD in pregnancy.


Conclusion

• Participants PANNA study

• Doctors and (research)nurses PANNA network

• Laboratory technicians dept. of pharmacy Radboudumc

• Drs. Pauline Bollen, Dr. Stein Schalkwijk, Drs. Vera Bukkems (Projectmanagers PANNA)

• Prof. Dr. David Burger (Principal Investigator PANNA)


Acknowledgements


Thank you for your attention

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