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Pharmacokinetics of Once Versus Twice Daily Darunavir in Pregnant HIV-Infected Women

Stek, Alice MD*; Best, Brookie M. PharmD, MAS; Wang, Jiajia MS; Capparelli, Edmund V. PharmD; Burchett, Sandra K. MD; Kreitchmann, Regis MD, PhD§; Rungruengthanakit, Kittipong MSc; Cressey, Tim R. PhD†,¶; Mofenson, Lynne M. MD#; Smith, Elizabeth MD**; Shapiro, David PhD; Mirochnick, Mark MD††

JAIDS Journal of Acquired Immune Deficiency Syndromes: September 1st, 2015 - Volume 70 - Issue 1 - p 33–41
doi: 10.1097/QAI.0000000000000668
Clinical Science
Free

Objective: To describe darunavir (DRV) pharmacokinetics with once-and twice-daily dosing during pregnancy and postpartum in HIV-infected women.

Design: Women were enrolled in International Maternal Pediatric Adolescent AIDS Clinical Trials Network Protocol P1026s, a prospective nonblinded study of antiretroviral pharmacokinetics in HIV-infected pregnant women that included separate cohorts receiving DRV/ritonavir dosed at either 800 mg/100 mg once daily or 600 mg/100 mg twice daily.

Methods: Intensive steady-state 12- or 24-hour pharmacokinetic profiles were performed during the second trimester, third trimester, and postpartum. DRV was measured using high-performance liquid chromatography (detection limit: 0.09 μg/mL).

Results: Pharmacokinetic data were available for 64 women (30 once daily and 34 twice daily dosing). Median DRV area under the concentration–time curve (AUC) and maximum concentration were significantly reduced during pregnancy with both dosing regimens compared with postpartum, whereas the last measurable concentration (Clast) was also reduced during pregnancy with once daily DRV. DRV AUC with once daily dosing was reduced by 38% during the second trimester and by 39% during the third trimester. With twice daily dosing, DRV AUC was reduced by 26% in both trimesters. The median (range) ratio of cord blood/maternal delivery DRV concentration in 32 paired samples was 0.18 (range: 0–0.82).

Conclusions: DRV exposure is reduced by pregnancy. To achieve DRV plasma concentrations during pregnancy equivalent to those seen in nonpregnant adults, an increased twice daily dose may be necessary. This may be especially important for treatment-experienced women who may have developed antiretroviral resistance mutations.

*Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, University of Southern California School of Medicine, Los Angeles, CA;

Department of Biostatistics, Statistical and Data Analysis Center, Harvard School of Public Health, Boston, MA;

Department of Medicine, Children's Hospital Boston, Boston, MA;

§HIV/AIDS Research Department, Irmandade da Santa Casa de Misericordia de Porto Alegre, Porto Alegre, Brazil;

Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand;

Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand;

#Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, DHHS, Bethesda, MD;

**National Institute of Allergy and Infectious Diseases, Bethesda, MD; and

††Department of Pediatrics, Boston University School of Medicine, Boston, MA.

Correspondence to: Mark Mirochnick, MD, Boston Medical Center, 771 Albany Street, Dowling 4N, Room 4111, Boston, MA 02118 (e-mail: markm@bu.edu).

Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) was provided by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) under Award Nos. UM1AI068632 (IMPAACT LOC), UM1AI068616 (IMPAACT SDMC), and UM1AI106716 (IMPAACT LC), with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institute of Mental Health (NIMH).

Presented in part at the third International Workshop on HIV Pediatrics, July 15–16, 2011, Rome, Italy.

Edmund Capparelli serves as a consultant to Gilead Sciences. The remaining authors have no conflicts of interest to disclose.

The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Received July 21, 2014

Accepted March 09, 2015

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INTRODUCTION

HIV-1–infected pregnant women commonly receive antiretroviral (ARV) drugs, both for their own health and for prevention of mother-to-child transmission of HIV-1 (HIV). Current US Public Health Service guidelines recommend that all ARV-naive pregnant women receive a combination ARV regimen including 2 nucleoside reverse transcriptase inhibitors and either a protease inhibitor or a nonnucleoside reverse transcriptase inhibitor.1

The physiological changes of pregnancy have a large impact on drug disposition.2 Previous studies have shown reduced exposure during pregnancy for many ARV drugs, in particular, protease inhibitors.3 Plasma concentrations of all HIV protease inhibitors studied during pregnancy, including lopinavir, nelfinavir, saquinavir, indinavir, fosamprenavir, and atazanavir, are decreased during pregnancy.4–9 Subtherapeutic ARV exposure during pregnancy may result in inadequate virologic control, increasing the risk of transmission of HIV to the infant and of maternal development of drug resistance mutations. Assessment of placental transfer of ARVs to the fetus is of critical importance, as transplacentally acquired ARVs expose the fetus to both potential benefit, from prophylaxis against HIV infection, and harm, from drug teratogenicity and/or toxicity.3 Before any ARV can be used safely and effectively in pregnancy, its pharmacology must be studied and well understood in pregnant women. Published data describing darunavir (DRV) pharmacokinetics during pregnancy are limited.10–16 The primary objectives of this study were to describe DRV pharmacokinetics in HIV-infected pregnant women receiving once- and twice-daily dosing and to determine whether standard doses of DRV produce equivalent drug exposure during pregnancy to that in nonpregnant adults. We also sought to evaluate transplacental passage of DRV by comparing concentrations in cord blood and maternal blood at delivery.

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METHODS

Study Population and Design

International Maternal Pediatric and Adolescent AIDS Clinical Trials (IMPAACT) Network Protocol P1026s is an ongoing international multicenter prospective opportunistic study to evaluate the pharmacokinetics of clinically prescribed ARV drugs in pregnant HIV-infected women (Clincialtrials.gov identifier NCT00042289). This report includes women receiving DRV with ritonavir at standard doses once and twice daily.

HIV-infected pregnant women receiving DRV 800 mg and ritonavir 100 mg orally once daily or DRV 600 mg and ritonavir 100 mg orally twice daily as part of clinical care before the beginning of the 35th week of pregnancy were eligible. The choice of additional ARVs and duration of treatment were determined by each subject's clinical care provider. Subjects received DRV for at least 2 weeks before pharmacokinetic sampling and planned to continue DRV until at least 6 weeks postpartum. Maternal exclusion criteria were current use of medications known to interfere with DRV disposition, multiple gestation, or clinical or laboratory toxicity that, in the opinion of the site investigator, would be likely to require a change in the ARV regimen during the study. All P1026 subjects at US sites were co-enrolled in P1025, a prospective cohort study of HIV-infected pregnant women receiving care at US IMPAACT sites. Local institutional review boards approved P1026s at all participating sites and P1025 at all US sites. All subjects provided signed informed consent before participation.

Subjects received ARV medications prescribed by their clinical care providers and all ARVs were dispensed by local pharmacies. Study mothers and their infants continued on the study until 6 months after delivery. Intensive DRV pharmacokinetic sampling was performed during the third trimester and repeated postpartum for all subjects. Women enrolling before 26 weeks gestation were also sampled during the second trimester. Samples obtained during pregnancy were assayed in real time, and each subject's physician was notified of the subject's DRV plasma concentrations and area under the concentration–time curve (AUC) within 2 weeks of collection. Individual physicians could elect a dosing modification if the AUC was below 70% of the median AUC in nonpregnant adults.17

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Clinical and Laboratory Monitoring

HIV-related laboratory testing was performed at each study visit if not available as part of routine clinical care. Maternal clinical data used for this analysis were maternal age, ethnicity, weight, concomitant medications, CD4+ lymphocyte, and HIV RNA assay results. HIV RNA assays were performed locally and had lower limits of detection ranging from 20 to 400 copies per milliliter. Maternal clinical and laboratory toxicities were assessed through clinical evaluations and laboratory assays on each pharmacokinetic sampling day, at delivery, and at 24 weeks postpartum. Infant birth weight, gestational age at birth, and HIV infection status were collected. All infants received physical examinations after birth, whereas infant laboratory evaluations were performed only as clinically indicated. The study team reviewed toxicity reports on monthly conference calls, although the subject's physician was responsible for toxicity management. The Division of AIDS (DAIDS)/NIAID Toxicity Table for Grading Severity of Adult Adverse Experience was used to grade adverse events for study subjects.18 All toxicities were followed through resolution or 24 weeks postpartum.

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Sample Collection

Plasma samples for pharmacokinetic evaluation were collected during the second (20 to 28 weeks gestation) and third (30–38 weeks) trimesters and between 6 and 12 weeks after delivery. Participants received a stable ARV regimen for at least 2 weeks before pharmacokinetic sampling. Participants were instructed to take their DRV at the same time each day for the 3 days before and on the day of the pharmacokinetic evaluations. Plasma samples were drawn at the antepartum and postpartum pharmacokinetic evaluation visits, starting immediately before an observed oral DRV dose at 1, 2, 4, 6, 8, and 12 hours after the witnessed dose. A 24 hour postdose sample was collected from once-daily dosing subjects. A single maternal plasma sample and an umbilical cord blood sample after cord clamping were collected at delivery.

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Darunavir Concentration Assays

DRV concentrations were measured in the Pediatric Clinical Pharmacology Laboratory of the University of California, San Diego, using a validated high-performance liquid chromatography assay.19 The laboratory is registered with the AIDS Clinical Trials Group (ACTG) Clinical Pharmacology Quality Assurance and Quality Control proficiency testing program and successfully passed (100%) the last 9 rounds of CPQA PT testing (September 2008–September 2012).20 At the lower limit of quantitation (0.09 μg/mL) over 6 days, the within-day precision (% coefficient of variation) ranged from 4.17% to 7.23% and accuracy (% deviation) ranged from −5.80% to 8.8%. The within-day precision for 4 validation samples above the lower limit of quantitation (high, middle, low, and extra-low concentrations) ranged from 1.33% to 5.87%. The within-day accuracy for the high, middle, low, and extra-low validation samples ranged from 9.07% to 5.33%. The mean recovery from plasma was 99.08%.

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Pharmacokinetic Analyses

The concentration data collected were analyzed by direct inspection to determine the predose concentration (Cpre-dose), the maximum plasma concentration (Cmax), the corresponding time (tmax), and the last measurable concentration (Clast). The AUC from time 0 to 12 or 24 hour postdose (AUC0–12 or AUC0–24) for DRV was estimated using the trapezoidal rule up to the last measurable concentration. Subjects whose predose DRV concentrations were nondetectable were deemed to have recent nonadherence, and AUC0–infinity was used to express exposure, with AUC after the last measured concentration estimated as C12/λz or C24/λz, where λz was the terminal slope of the log concentration versus time curve. The minimum exposure targets were an AUC0–24 of at least 56.5 μg·h·mL−1 for once-daily dosing and an AUC0–12 of at least 43.6 μg·h·mL−1 for twice-daily dosing, which were 70% of the average AUC in nonpregnant adults contained in the DRV package insert at the time this study arm was developed.17 The half-life (t1/2) was calculated as 0.693/λz. Apparent clearance (CL/F) from plasma was calculated as the dose divided by AUC. The apparent volume of distribution (Vd/F) was determined as CL/F divided by λz. AUC and CL/F were also computed using a 1-compartment model in WinNonlin (Pharsight Corp., St. Louis, MO). Pharmacokinetic parameters derived from each approach were compared to assess potential limitations of each methodology.

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Statistical Analyses

The target sample sizes were 25 women per study arm with evaluable third trimester pharmacokinetic data, of whom at least 12 had evaluable second trimester data. The third trimester sample size of 25 was chosen to provide at least 80% probability of concluding that the exposure of the pregnant population is lower than that of the nonpregnant population, when the value of the 10th percentile from the nonpregnant population has a true cumulative probability of 30% or higher in the pregnant population (ie, when at least 30% of pregnant women will have exposure below the 10th percentile for the nonpregnant population). The final sample sizes exceeded the enrollment targets because of continued enrollment during the period between the obtaining of informed consent and the availability of pharmacokinetic data.

The study design incorporated a 2-stage analysis approach. Each individual woman's DRV exposure during pregnancy was determined in real time and compared with the AUC estimated for a nonpregnant adult HIV-1–infected historical control population from the literature and was promptly reported to each subject's physician.17 Each subject's physician had the option to adjust the dose based on the pharmacokinetic results. A stopping criterion to trigger an evaluation of the adequacy of drug exposure was predefined as 6 of 25 women (24%; exact 80% confidence limits: 13% to 38%) falling below the target AUC. The goal was to prevent excess accrual to a cohort with known inadequate ARV exposure. The statistical rationale for this early stopping criterion has been previously described.4

Descriptive statistics were calculated for pharmacokinetic parameters of interest during each study period. DRV pharmacokinetic parameters during the second trimester versus postpartum and during the third trimester versus postpartum were compared at the within-subject level using the Wilcoxon signed-rank test, with a P value of <0.05 considered to indicate statistical significance.

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RESULTS

Sixty-six pregnant women were enrolled, of whom 34 received DRV/ritonavir twice daily and 32 once daily. Thirty women enrolled in the second trimester and 36 in the third trimester. Two of the second trimester enrollees delivered prematurely before third trimester sampling could be completed. Twenty-eight subjects (15 receiving once-daily dosing and 13 receiving twice-daily dosing) successfully completed second trimester pharmacokinetic sampling and 64 (30 receiving once-daily dosing and 34 receiving twice-daily dosing) successfully completed third trimester sampling. Fifty-two subjects successfully completed postpartum sampling, but 2 subjects (1 subject in each dosing group) had no detectable DRV concentrations and their postpartum data are not included in the summary pharmacokinetic statistics. The clinical characteristics of the study subjects are summarized in Table 1.

TABLE 1

TABLE 1

Figure 1 depicts the median antepartum and postpartum DRV concentration–time curves. DRV pharmacokinetic parameters are presented in Table 2. For the subjects receiving once-daily dosing, compared with postpartum, second and third trimester median AUC0–24 were reduced by 38% and 39%, median Cmax was reduced by 17% and 29%, and median Clast (24 hours) was reduced by 63% and 57%, respectively. The frequency of subjects meeting the AUC0–24 target for once-daily dosing was reduced during the second trimester [9/15 (60%)] and the third trimester [19/30 (63%)] compared with postpartum [22/24 (92%)]. Clast (24 hours) exceeded the DRV EC50 for wild-type HIV of 0.06 μg/mL in all but 2 once-daily subjects, 1 each in the second and third trimesters.

FIGURE 1

FIGURE 1

TABLE 2

TABLE 2

For the subjects receiving twice-daily dosing, compared with postpartum, second and third trimester median AUC0–12 were reduced by 26% and median Cmax was reduced by 28% and 29%, respectively, whereas there were no significant differences in Clast. The frequency of subjects meeting the AUC0–12 target for twice-daily dosing was 7/13 (54%) during the second trimester and 19/34 (56%) during the third trimester, compared with 22/27 (81%) postpartum; these differences reached statistical significance only for the third trimester to postpartum comparison. Clast exceeded the DRV EC50 for wild-type HIV of 0.06 μg/mL in all twice-daily subjects except 1 postpartum subject.

No care provider elected to increase the DRV dose for any subject in either arm. Graphs presenting DRV AUC and Clast concentrations for individual subjects across sampling times are depicted in Figure 2. The one-compartment analysis yielded similar DRV exposure parameters to the noncompartmental analysis (data not presented).

FIGURE 2

FIGURE 2

Median (interquartile range) ritonavir pharmacokinetic parameters with once-daily dosing during the second trimester, third trimester, and postpartum periods were AUC0–24: 3.7 μg·h·mL−1 (2.5–4.7), 3.7 μg·h·mL−1 (2.3–5.0), 8.2 μg·h·mL−1 (5.8–10.8); Cmax: 0.29 μg/mL (0.22–0.41), 0.27 μg/mL (0.22–0.42), 0.64 μg/mL (0.35–0.90); Clast <0.09 μg/mL (<0.09–0.09), <0.09 μg/mL (<0.09–0.08), 0.09 μg/mL (<0.09–0.14). With twice-daily dosing, median (interquartile range) ritonavir pharmacokinetic parameters during the second trimester, third trimester, and postpartum periods were AUC0–12: 3.9 μg·h·mL−1 (3.1–5.2), 3.8 μg·h·mL−1 (3.1–4.8), 5.6 μg·h·mL−1 (3.7–11.3); Cmax: 0.47 μg/mL (0.32–0.64), 0.46 μg/mL (0.36–0.67), 0.63 μg/mL (0.438–1.08); Clast: 0.16 μg/mL (0.14–0.24), 0.18 μg/mL (0.11–0.25), 0.20 μg/mL (0.12–0.35).

Maternal plasma samples at delivery and umbilical cord blood samples were collected from 43 subjects. DRV concentration was below the assay limit of quantitation in 11 maternal and 15 cord blood samples. When maternal plasma DRV concentration at delivery was above the limit of quantitation, the median (range) DRV cord blood concentration was 0.41 μg/mL (range: <0.09–1.55 μg/mL), maternal plasma delivery concentration was 1.98 μg/mL (range: 0.19–5.62 μg/mL), ratio of cord blood to maternal delivery concentration was 0.18 (range: 0–0.82), and the median time between administration of the last antenatal DRV dose and delivery was 15.1 hour (range: 2.2–43.9 hours). Figure 3 presents the cord blood and maternal delivery DRV concentrations plotted against the time between maternal dosing and delivery.

FIGURE 3

FIGURE 3

Overall, DRV was well tolerated during pregnancy and postpartum. No subjects indicated side effects of DRV as a reason for discontinuation. There was 1 toxicity thought by a care provider to be related to study treatment, life-threatening grade 4 anemia in 1 subject, although the study team thought it most likely due to concomitant nucleoside reverse transcriptase inhibitor use. Six subjects had toxicities thought to be possibly related to DRV treatment, including 3 with grade 2 liver function test elevations, 1 with intrauterine growth restriction, 1 with grade 2 hypercholesterolemia, and 1 with gestational diabetes.

Study infants were delivered at a median of 38.6 weeks of gestation (range: 31.6–42.4 weeks) with a median birth weight of 3022 g (range: 1800–4560 g) and a median length of 49 cm (range: 41–54.6 cm). Congenital anomalies were reported in 9 infants: 2 cases of postaxial polydactyly (supernumerary digit), and 1 case each of congenital cystic adenomatoid malformation (congenital pulmonary airway malformation), cardiac murmur, patent foramen ovale, patent ductus arteriosus with the right ventricular hypertrophy, genitourinary chordee, atrial septal defect, ventricular septal defect, and a hearing impairment. With the exception of the cardiac murmur and the patent foramen ovale, which were thought to be possibly related, these were deemed not related to DRV exposure by the clinical care providers and by the study team.

No infant HIV infection data are available for 3 infants whose mothers withdrew from the study shortly after delivery. Of the remaining 63 infants, 1 was HIV infected. This infant had an initial positive HIV RNA on day 3 of life, subsequently confirmed with a second test, and also had congenital toxoplasmosis. The infant was born with weight appropriate for gestational age at 38-week gestation to a mother on the twice-daily arm who enrolled in the third trimester and had an HIV RNA of 66,142 copies per milliliter at delivery. Her predose DRV concentration on the day of her third trimester pharmacokinetic assessment was below the assay limit of detection, suggesting poor adherence. Fifty-eight infants were confirmed uninfected and 4 had negative tests through age 2–9 weeks with no further testing available.

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DISCUSSION

DRV is an HIV protease inhibitor recommended for use as a first-line agent in combination with ritonavir dosed once daily for the treatment of ARV-naive HIV-infected adults and dosed twice daily for the treatment of ARV-experienced adults with at least 1 DRV resistance mutation.22 The physiological changes associated with pregnancy have been shown to decrease drug exposure of other HIV protease inhibitors by 28%–41% compared with postpartum.4–9 Our study is the first to describe DRV pharmacokinetics in a large group of pregnant women receiving both once- and twice-daily administration. Among our subjects, median DRV AUC in the second and third trimesters decreased 38%–39% with once-daily dosing and 26% with twice-daily dosing compared with postpartum. These results are consistent with previously published case reports and smaller series of patients.10–16 Zorrilla et al15 reported a decrease of 17%–24% in DRV AUC in 14 women dosed twice daily in the second and third trimesters. Colbers et al16 reported a mean decrease in DRV AUC of 34% in 6 women with twice-daily dosing and 22% in 18 women with once-daily dosing in the third trimester. Our data are also consistent with a recent presentation describing DRV exposure in pregnant women. Courbon et al described DRV trough concentrations in 33 mostly African women in France receiving once- and twice-daily dosing. Trough DRV concentrations were decreased 20%–25% in the second and third trimesters compared with the first trimester and were lower with once-daily dosing than with twice-daily dosing.23

Although trough concentration is considered the pharmacokinetic parameter that correlates best with protease inhibitor efficacy, trough concentration targets have not been established for DRV.24 The DRV EC50 of wild type HIV is 0.06 μg/mL, below the lower limit of sensitivity of 0.09 μg/mL of the assay used in this study.24 Resistance of HIV to protease inhibitors develops with accumulation of multiple mutations in the HIV genome, so that trough concentrations effective in treatment-naive subjects who lack prior exposure to protease inhibitors may not be effective in treatment-experienced subjects with HIV strains that include protease resistance mutations. DRV trough concentrations are lower with once-daily than twice-daily dosing, and once-daily dosing is recommended only for ARV-naive patients and for treatment-experienced patients with no DRV resistance mutations.22 Our once-daily dosing subjects had median trough concentrations during the second and third trimester of 0.99 and 1.17 μg/mL, compared with median troughs of 2.71 μg/mL in the same women postpartum and 2.16–2.28 μg/mL in clinical trials of once-daily DRV in HIV-infected adults.17 Median trough concentrations were less affected by pregnancy in our twice-daily dosing subjects, who had second and third trimester median troughs of 2.12 and 2.22 μg/mL, compared with 2.51 μg/mL postpartum and 3.39–3.58 μg/mL in clinical trials of HIV-infected adults receiving twice-daily DRV.17

It is difficult to determine the clinical significance of a reduction in DRV exposure of the magnitude we observed and whether HIV-infected pregnant women would benefit from use of an increased dose during pregnancy. In our study, HIV RNA at delivery was below 400 copies per milliliter in 90% of once-daily dosing subjects and 81% of twice-daily dosing subjects. In the study by Zorrilla et al,15 3 of 14 subjects had detectable HIV RNA (>50 copies per milliliter) during pregnancy and 2 of these subjects became undetectable during postpartum follow-up while continuing on DRV. In the study by Colbers et al25 of pregnant women receiving once-daily dosing, 73% had an HIV RNA below 50 copies per milliliter and 93% below 1000 copies per milliliter approaching delivery. There were no infected infants born to the 12 mothers in the Zorrilla et al15 study who remained on therapy at delivery or the 15 mothers in the Colbers et al25 study. In our study, 1 infant was infected out of 63 with at least some virologic testing results available.

The impact of ARV use during pregnancy on the durability of maternal ARV treatment continuing after delivery should also be considered in determining ARV doses during pregnancy. It is unknown whether a sustained period of decreased DRV exposure during pregnancy could result in a more rapid development of resistant virus and treatment failure during long-term postnatal treatment.

Protease inhibitors are highly protein-bound drugs, and plasma protein binding of drugs generally decreases during pregnancy because of decreases in the quantity of albumin and α-1-acid glycoprotein.26 As a result, concentration of free (unbound) drug tends to be higher in pregnant women compared with nonpregnant women with the same total drug concentration. Because free drug is the pharmacologically active fraction of drug in plasma, reductions in protein binding during pregnancy have the potential to at least partially compensate for the reduction in total plasma protease inhibitor concentrations, as has been shown for lopinavir.27–29 Interpretation of the lopinavir protein-binding data has been controversial, with some authors concluding that the protein-binding changes negate the impact of differences in total lopinavir concentration during pregnancy, while others disagree.27–30 Concentrations of free DRV during pregnancy have been reported in 2 studies. Zorrilla et al15 reported free DRV concentrations in 6 second trimester, 7 third trimester, and 11 postpartum subjects. Although total AUC was significantly decreased during pregnancy, there were no significant differences in free DRV AUC or Cmin, or in DRV-free fraction. Colbers et al16 reported no difference in mean (95% confidence interval) DRV-free fraction in 19 women during pregnancy compared with 14 women postpartum [12% (95% CI: 11% to 14%) in the third trimester and 10% (95% CI: 7% to 13%) postpartum]. These studies are too small and lack sufficient clinical correlations to allow definitive conclusions as to whether changes in protein binding during pregnancy may mitigate the decreases in total plasma DRV concentrations. However, the free fraction of DRV is much greater than that of lopinavir, which has a free fraction in nonpregnant adults of 1%–2%, suggesting that changes in protein binding associated with pregnancy are more likely to have a significant impact on free drug concentration of lopinavir than of DRV.31

The magnitude of the reduction in DRV exposure associated with pregnancy that we observed is consistent with the decreases that have been observed for other protease inhibitors.5–9 For some of these drugs, including lopinavir, atazanavir, and nelfinavir, use of increased doses in pregnancy has been shown to result in plasma concentrations equivalent to those seen in nonpregnant adults receiving standard dosing.32–34 Two randomized studies of standard versus increased dose lopinavir in pregnancy suggest that increased lopinavir doses may be beneficial for pregnant women with a detectable viral load at initiation of treatment in pregnancy or with detectable lopinavir resistance mutations.35,36 The package insert for atazanavir, the only protease inhibitor approved in the United States for use in pregnancy, includes a recommendation for an increased dose for treatment-experienced pregnant women in the second or third trimester who are also receiving tenofovir or an H2-receptor antagonist, which have been shown to reduce atazanavir exposure.37 There are no data on DRV pharmacokinetics or clinical outcomes with the use of an increased dose in pregnancy, and an increased twice-daily DRV dose (800 mg or 900 mg DRV with 100 mg ritonavir) is currently under study in another arm of P1026s. Ritonavir exposure was reduced during pregnancy in our subjects, consistent with the reduction seen in other pregnancy studies of ritonavir-boosted protease inhibitors in pregnant women.15,32,33 Although it is not known if use of an increased ritonavir dose would increase DRV exposure during pregnancy, the poor tolerability of ritonavir makes increasing the ritonavir dose unattractive to pregnant women and their care providers.

DRV was well tolerated in our subjects, who demonstrated little toxicity attributed to DRV use. Placental transfer of DRV was poor, as has been demonstrated for other protease inhibitors.38 The median ratio of maternal to cord blood DRV was 0.18, consistent with that seen in previous studies, and this ratio reached a steady state at around 8 hours after administration of the last maternal dose before delivery.15,25

There are several limitations to our study. Our study used an opportunistic design, enrolling pregnant women receiving DRV as part of clinical care, and enrolled a very heterogeneous population. Women enrolled at various stages of pregnancy and with varying past histories of ARV use, ranging from none to years of treatment with multiple regimens. Their duration of DRV treatment at the time of third trimester sampling ranged from 2 weeks to nearly 5 years. Our study population was biased toward those who tolerated and responded well to DRV therapy, as pregnant women with early DRV toxicity or lack of efficacy may have been switched to other ARVs and would not have been eligible for enrollment. Clinical care providers determined whether subjects received once- or twice-daily dosing and were responsible for making adjustments to the ARV regimens because of drug toxicity and therapeutic response. Our study included no rigorous measure of adherence, although inspection of the intensive pharmacokinetic profiles did reveal whether subjects were at steady state at the time of sampling. In addition, we measured concentrations of total but not free DRV, so we can provide no new data to address the question of the impact of protein-binding changes on free DRV concentrations during pregnancy.

In summary, our study of a large number of women demonstrates a significant reduction in DRV plasma concentrations during pregnancy with once- and twice-daily dosing, consistent with reductions seen with other proteases inhibitors during pregnancy. Given the absence of established DRV trough concentration targets, it is reasonable to use typical plasma concentrations seen in nonpregnant adults as a therapeutic target when DRV is used during pregnancy. To achieve DRV plasma concentrations during pregnancy equivalent to those seen in nonpregnant adults, an increased twice-daily dose may be necessary. This may be especially important for treatment-experienced women who may have developed ARV resistance mutations.

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ACKNOWLEDGMENTS

The authors thank the study participants and their families. In addition to the authors, members of the IMPAACT P1026s protocol team include Francesca Aweeka, Michael Basar, Emily Barr, Mark Byroads, Nantasak Chotivanich, Lisa M. Frenkel, Kathy George, Elizabeth Hawkins, Kathleen Adriane Hernandez, Amy Jennings, Rita Patel, and Pra-ornsuda Sukrakanchana. The authors also thank the following investigators and staff at the enrolling sites: New Jersey Medical School CRS (Linda Bettica, RN; Charmane Calilap-Bernardo, MA, PNPC; Arlene Bardeguez, MD, MPH); Texas Children's Hospital CRS (Shelley Buschur, RN, CNM; Chivon Jackson, RN, BSN, ADN; Mary Paul, MD); Columbia CRS (Philip La Russa, MD); University of Miami Pediatric Perinatal HIV/AIDS CRS (Claudia Florez, MD; Patricia Bryan, BSN, MPH; Monica Stone, MD); University of California San Diego Mother-Child-Adolescent Program CRS [Andrew D. Hull, MD; Caffery, RN, MSN; Stephen A. Spector, MD]; Duke University Medical Center CRS (Joan Wilson, RN, BSN, MPH; Julieta Giner, RN, ACRN; Margaret A. Donnelly, PA-C); New York University, New York NICHD CRS (Nagamah Deygoo, MD; Aditya Kaul, MD; William Borkowsky, MD); Jacobi Medical Center Bronx NICHD CRS (Mindy Katz, MD; Raphaelle Auguste, RN; Andrew Wiznia, MD); University of South Florida—Tampa NICHD CRS (Karen L. Bruder, MD; Gail Lewis, RN; Denise Casey, RN); University of Southern California School of Medicine—Los Angeles County NICHD CRS (Françoise Kamer, MD; LaShonda Spencer, MD; James Homans, MD); University of Colorado Denver NICHD CRS (Torri Metz, MD; Jenna Wallace, MSW; Alisa Katai, MHA); Hospital dos Servidores Rio de Janeiro NICHD CRS (Esau C. Joao, MD, PhD; Plinio Tostes Berardo Carneiro da Cunha, MD, PhD; Maria Isabel Fragoso da Silveira Gouvêa, MD); Hospital General de Agudos Buenos Aires NICHD CRS (Marcelo H. Losso, MD; Silvina A. Ivalo, MD; Alejandro Hakim, MD); Miller Children's Hospital NICHD CRS (Audra Deveikis, MD; Jagmohan Batra, MD; Janielle Jackson Alvarez, RN); Hospital Santa Casa Porto Alegre Brazil NICHD CRS (Regis Kreitchmann, PhD, MD; Debora Fernandes Coelho, MN, PhD; Marcelo Comerlato Scotta, MSc, MD); St Jude CRS (Katherine M. Knapp, MD; Nina Sublette, FNP, PhD; Thomas Wride, MS); University of Puerto Rico Pediatric HIV/AIDS Research Program CRS (Irma L. Febo, MD; Ruth Santos, RN, MPH; Vivian Tamayo, MD); The Children's Hospital of Philadelphia (Steven D. Douglas, MD; Carol A. Vincent, PhD, CRNP; Samuel Parry, MD); Bronx-Lebanon Hospital CRS (Jenny Gutierrez, MD; Mary Elizabeth Vachon, MPH; Murli Purswani, MD); Siriraj Hospital Mahidol University, Bangkok, Thailand CRS (Thanomsak Anekthananon, MD; Amphan Chalermchokcharoenkit, MD; Kulkanya Chokephaibulkit, MD).

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REFERENCES

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Keywords:

darunavir; pregnancy; HIV; pharmacokinetics

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