AAC Accepted Manuscript Posted Online 6 April 2015 Antimicrob. Agents Chemother. doi:10.1128/AAC.00173-15 Copyright © 2015, American Society for Microbiology. All Rights Reserved.

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Pharmacokinetic of dolutegravir in a premature neonate after HIV

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treatment intensification during pregnancy

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Running title: Dolutegravir pharmacokinetic in a premature neonate

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J.B. Paina, M.P. Lêa, M. Caserisb, C. Amielc,d, L. Lassele, C. Charpentierf,g, A. Desnoyera, C.

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Farnouxh, G. Pialouxd, D. Descampsf,g, G. Peytavina,g

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a

AP-HP, Clinical Pharmacology Department, Bichat Hospital, F-75018, Paris, France

b

AP-HP, General Pediatry, Robert Debré Hospital, Paris, France

c

AP-HP, Virology Department, Tenon Hospital, Paris, France

d

AP-HP, UPMC Univ Paris 06, UMRS CR7, Inserm U1135, 75013 Paris, France

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AP-HP, Infectious Diseases Unit, Tenon Hospital, Paris, France

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AP-HP, Virology Department, Bichat Hospital, F-75018, Paris, France

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IAME, UMR 1137, Univ Paris Diderot, Sorbonne Paris Cité and UMR 1137, INSERM, F-

75018, Paris, France h

AP-HP, Neonatology Department, Robert Debré Hospital, Paris, France

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Corresponding author:

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Dr Minh Patrick Lê

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[email protected]

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Keywords: dolutegravir, integrase inhibitors, neonate, HIV, pregnancy.

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ABSTRACT (74/75 words)

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We describe dolutegravir (DTG) pharmacokinetic in a premature neonate after maternal

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intensification of antiretroviral (ARV) regimen by adding DTG. During the last 2 weeks of

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pregnancy, ARV were tenofovir/emtricitabine, atazanavir/ritonavir and DTG (50 mg once-

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daily). From the drug interaction between atazanavir and DTG via CYP3A4 and UGT1A1

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and placental efflux transporter inhibitions and considering the probable enzymatic

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immaturity, the DTG elimination half-life was estimated to be four-fold higher in the neonate

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than in adults.

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FULL TEXT

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Dolutegravir (DTG) is a novel, potent, HIV-1–integrase strand transfer inhibitor; data for

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pregnant women are limited. From animal reproduction studies failing to demonstrate any risk

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to the fetus and with lack of adequate and well-controlled studies in pregnant women, DTG

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was classified as a category B drug by the US Food and Drug Administration (1).

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Consequently, a DTG-containing regimen could be used during pregnancy to sharply decrease

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the plasma HIV-1 RNA level (plasma viral load [pVL]) near delivery in late HIV infection

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presenters. It could also be used for infection with viruses harboring resistance substitutions in

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the integrase coding region with limited alternative antiretroviral treatment (ARV) to prevent

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the risk of mother-to-child transmission.

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Here we report on DTG intensification in a 35-year-old African woman with HIV-1

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infection since 2002, well controlled until pregnancy, who was admitted in emergency at

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hospital for premature rupture of the membranes at 35 weeks’ gestation. According to the

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national guidelines in France (2), the HIV infection was successfully treated with tenofovir

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disoproxil

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atazanavir/ritonavir (ATV/RTV, 300/100 mg once daily), with undetectable pVL and

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approximately 500 CD4/mm3 until pregnancy. At 22 and 32 weeks’ gestation, for no apparent

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reason, the pVL rebounded, at 279 and 453 copies/mL, respectively.

fumarate/emtricitabine

(TDF/FTC,

300/200

mg

once

daily)

and

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To document the safety and adherence to ARV, plasma concentrations were

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determined by ultra–performance liquid chromatography with tandem mass spectrometry

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(Waters Acquity UPLC-TQD, Milford, MA, USA) after sample pre-treatment as described

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(3). At 26 weeks’ gestation, maternal ARV concentrations 24 hr post-dose (C24h) were as

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follows: ATV, 1,319 ng/mL; RTV, 48 ng/mL; FTC, 91 ng/mL and TFV, 50 ng/mL. FTC and

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TFV C24h were considered adequate and ATV C24h was considered active but elevated,

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according to the 200-850 ng/mL efficacy-tolerance interval (2). At the time of virological

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failure, the genotypic resistance test of the HIV-1 subtype CRF06_cpx revealed four

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thymidine-associated substitutions (M41L, K70R, L210W and T215Y) and an M184V

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substitution conferring resistance to FTC and possible resistance to TFV. With these results

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and with the absence of a genotypic resistance test for integrase coding region and to retain a

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once-daily regimen, DTG, 50 mg once daily, was added to therapy at 33 weeks’ gestation.

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At 35 weeks’ gestation, 2 days before delivery and 2 weeks after DTG intensification,

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the maternal steady-state total and unbound ATV C24h were 972 and 65 ng/mL, respectively,

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and DTG C24h 3,007 and 44 ng/mL, respectively. The maternal free fractions were calculated

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as 6.6% and 1.5% for ATV and DTG, respectively. The total DTG C24h was interpreted

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according to the supposed 1,000 ng/mL effective threshold predictive of the virological

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response in the Sailing study (4). C24h of RTV, at 86 ng/mL; FTC, 221 ng/mL and TFV, 85

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ng/mL were considered adequate.

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Delivery was by caesarian section, 48 hr after hospitalization. The newborn son

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appeared hypotrophic, with weight 1,600 g; length 43 cm, and APGAR score 10/10. He

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received 5 days of phototherapy from day 4 to 9; the maximum total bilirubinemia was 175

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μmol/L on day 5. At delivery, the maternal pVL was undetectable and the cord blood was

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negative for proviral DNA as assessed by real-time PCR for POL and LTR sequences (limit

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of detection < 10 copies/million peripheral blood mononuclear cells).

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In the neonate, on day 1, post-exposure prophylaxis was started with intravenous

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zidovudine, 2 mg/kg twice a day. At age 3 and 5 days, the DTG plasma concentrations

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resulting from maternal placental transfer were 1,803 and 1,322 ng/mL, respectively. In both

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samples, ATV plasma concentration was < 10 ng/mL. At day 5, unbound DTG plasma

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concentration was 16 ng/mL, corresponding to a free fraction of 1.2%. At day 9, total and

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unbound DTG plasma concentrations were 428 and < 10 ng/mL, respectively. Both results of

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free fractions for DTG in the neonate were consistent with values in adults (1). At day 18 after

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delivery, the total DTG plasma concentration was < 10 ng/mL, demonstrating complete DTG

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elimination in the neonate.

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In this premature neonate, the calculated terminal plasma half-life of DTG, based on a

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one-phase pharmacokinetic elimination, was approximately 46 hr. With a two-phase

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elimination model, the calculated half-lives were 68 hr (first) and 40 hr (terminal). With this

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last pharmacokinetic model, the DTG plasma concentration in cord blood might be

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extrapolated to approximately 4,051 ng/mL at delivery. As an illustration, 2 days before

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delivery, total and unbound maternal DTG C24h were 3,007 and 44 ng/mL, respectively. The

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materno-fetal ratio of DTG plasma concentration was estimated to 1.3, (using the total cord

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blood DTG plasma concentration at delivery and the last measured total maternal DTG C24h,

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2 days before delivery), for a probable accumulation in the fetal compartment. Knowing that

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20% of total ATV crosses the placenta (5), we estimated the ATV plasma concentration in

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cord blood at approximately 194 ng/mL.

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To our knowledge, this is the first case report demonstrating an unexpected placental

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transfer of DTG with fetal accumulation then slow neonatal clearance. Several mechanistic

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hypotheses might explain this DTG placental transfer as the drug interaction between ATV

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and DTG in both the mother and neonate (1,6). ATV acts as a perpetrator of the DTG

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pharmacokinetics, leading to increased half-lives in both the mother and neonate via

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inhibition of CYP3A4 and UGT1A1, corresponding to the first slope of the DTG elimination

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in the neonate with the longer half-life (Figure 1). In healthy adults, trough DTG plasma

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concentration is 121% increased and the half-life reached 24 hr, for a two-fold increased value

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(7). ATV is also an inhibitor of placental ABC transporter (P-glycoprotein), which possibly

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limits the fetal efflux of DTG (8,9). Moreover, the premature glucuronyl-transferase

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immaturity might increase the neonatal DTG accumulation, more than the extrapolation of

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maternal free fraction would predict, which might explain the terminal half-life of DTG.

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Finally, and despite the unexpected DTG plasma overexposure and the four-fold

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increase in DTG half-life in the premature neonate as compared to adults, the tolerance was

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good.

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Words: 977/1000

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ACKNOWLEDGMENTS

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None to declare.

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919.

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150 Plasma concentration (ng/mL)

Cord Blood Mother

10000

Premature neonate

DTG Total: 3007 ng/mL Unbound: 44ng/mL DTG Total: 4051 ng/mL DTG Total: 1803 ng/mL DTG Total:1322 ng/mL Unbound: 16 ng/mL

1000

ATV Total: 972 ng/mL Unbound 65 ng/mL

DTG Total: 428 ng/mL Unbound:

Pharmacokinetics of dolutegravir in a premature neonate after HIV treatment intensification during pregnancy.

We describe the pharmacokinetics of dolutegravir (DTG) in a premature neonate after maternal intensification of an antiretroviral (ARV) regimen by add...
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