Pharmacokinetics of Atazanavir Boosted With Cobicistat in Pregnant and Postpartum Women With HIV

Jeremiah D. Momper, PharmD, PhD; Jiajia Wang, MS; Alice Stek, MD; David E. Shapiro, PhD; Kathleen M. Powis, MD; Mary E. Paul, MD; Martina L. Badell, MD; Renee Browning, RN, MSN; Nahida Chakhtoura, MD; Kayla Denson, PhD; Kittipong Rungruengthanakit, MD; Kathleen George, MPH; Edmund V. Capparelli, PharmD; Mark Mirochnick, MD; Brookie M. Best, PharmD, MAS

Disclosures

J Acquir Immune Defic Syndr. 2022;89(3):303-309. 

In This Article

Methods

Study Population and Design

IMPAACT P1026s, "Pharmacokinetic Properties of Antiretroviral and Related Drugs during Pregnancy and Postpartum" (ClinicalTrials.gov NCT00042289), was a nonrandomized, open-label, parallel-group, multicenter, phase IV prospective study. The study included an arm for pregnant individuals living with HIV receiving fixed-dose combination atazanavir 300 mg/cobicistat 150 mg once daily (EVOTAZ; Bristol Myers Squibb Company, Princeton, NJ) who enrolled between April 11, 2016, and July 23, 2019. Atazanavir/cobicistat was prescribed for clinical care as part of participant's antiretroviral regimen. Participants had to be between 20 and 38 weeks' gestation, be stable on their antiretroviral regimen for at least 2 weeks, and intend to continue the same regimen through 6–12 weeks postpartum. The maternal exclusion criteria were multiple gestation, a clinical or laboratory toxicity necessitating a medication change during the study, and the use of specific medications known to interact with atazanavir or cobicistat.

Each study site received local institutional review board approval. All participants gave informed consent before study participation. Medications were prescribed by each participant's clinical care provider. Pharmacokinetic sampling was performed during the third trimester (30–38 weeks' gestation) and postpartum, as well as the second trimester (20–26 weeks' gestation) for participants enrolling before 26 weeks' gestation. Samples collected during pregnancy were assayed in real time with results reported to each study participant and her clinician.

Infant enrollment occurred immediately after maternal enrollment with maternal consent, with eligibility confirmed at birth. The infant inclusion criteria were birth weight >1000 grams, singleton delivery, and maternal enrollment in P1026s. The infant exclusion criteria included presence of a severe congenital malformation or medical condition that would interfere with study participation as deemed by site clinicians or use of specific medications known to interfere with atazanavir or cobicistat disposition.

Clinical and Laboratory Monitoring

Each study visit included monitoring of HIV-1 RNA, CD4+ lymphocyte cell count, hematology, and serum biochemistry tests. All infants received physical examinations after birth, and laboratory evaluations were performed only if clinically indicated. All infant HIV test results performed as part of clinical care were recorded through chart abstraction. Infants with positive HIV test results were classified as infected. Infants with 2 negative HIV test results, one after age 1 month and one after age 4 months, were classified as uninfected. Infants with negative test results who did not meet these criteria were classified as either uninfected based on best available data or indeterminate, depending on the available HIV test data. Adverse events were reported at each study visit, and management was determined by each participant's clinician. The National Institute of Allergy and Infectious Diseases (NIAID), Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events version 2.0, dated November 2014, was used to grade adverse event severity.

Sample Collection

Intensive 24-hour pharmacokinetic evaluations were performed during the second trimester (20–26 weeks' gestation), third trimester (30–38 weeks' gestation), and postpartum (6–12 weeks after delivery). Requirements before pharmacokinetic sampling were self-reported atazanavir and cobicistat adherence for 2 weeks and consistent dosing times for the last 3 doses. On sampling days, the predose sample was drawn and study medications were administered under observation. Postdose samples were drawn at 1, 2, 4, 6, 8, 12, and 24 hours. At delivery, cord blood and maternal plasma samples were collected when possible. Four plasma samples were collected from study infants at 2–10 hours, 18–28 hours, 36–72 hours, and 5–9 days after birth.

Atazanavir and Cobicistat Plasma Concentration Measurements

Quantitative determination of atazanavir and cobicistat in human plasma was accomplished by the use of protein precipitation and high-pressure liquid chromatography with UV detection and high-performance liquid chromatography (HPLC) with tandem mass spectrometry detection, respectively. Atazanavir was precipitated from 200 μL of plasma with 240 μL of 100% acetonitrile (MeCN). A total of 50 μL of supernatant was injected directly onto a C-18 reversed phase HPLC column (Ace 5, 4.6 × 150 mm). Atazanavir was separated isocratically using a mobile phase consisting of 43% buffer (10 mM potassium phosphate buffer, pH 3.0–3.1) and 57% ACN at a flow rate of 0.75 mL/min. UV detection was at 245 nm. The mean recovery of drug from plasma was 105.77%. The method was linear over the range of 0.039–10.0 μg/mL. Quantitation was by external calibration standards used to generate a curve using a least-squares linear regression algorithm to plot the peak area versus concentration with 1/response weighting. The lower limit of quantification of the assay was 0.039 μg/mL.

Cobicistat was precipitated from 10 μL of plasma with 300 μL of 100% acetonitrile (MeCN) plus the internal standard [2H8]-cobicistat (D8-cobicistat) (300 ng/mL). A total of 5 μL of supernatant was injected directly onto a C-18 reversed phase HPLC column (Mac-Mod Ace-5, 2.1 × 150 mm). Cobicistat was eluted using a gradient mobile phase consisting of 90% 0.1% formic acid in water and 10% 0.1% formic acid in MeCN to 5% 0.1% formic acid in water and 95% 0.1% formic acid in MeCN at a flow rate of 0.6 mL/min to 0.8 mL/min. MS/MS detection was made in positive electrospray ionization mode with MRM monitoring of transitions (776.5→606.2) and (784.5→614.5) for cobicistat and D8-cobicistat, respectively. The mean recovery efficiency of drug from plasma was 100.8%. The method had a dynamic range of 4.9–2500 ng/mL. Calibration standards are used to generate a curve using a linear regression algorithm to plot the peak area ratio of cobicistat/D8-cobicistat versus concentration with 1/x weighting, over the full dynamic range of analyte concentrations. Concentrations of incurred and quality control samples are calculated with the same regression analysis.

Pharmacokinetic Analysis

Atazanavir and cobicistat maximum, minimum, and last plasma concentrations (Cmax, Cmin, and C24) along with corresponding time points (Tmax and Tmin) were observed directly. Steady-state area under the plasma concentration versus time curve over the 24-hour dosing interval (AUC0–24) was estimated with the trapezoidal rule. The terminal elimination half-life (t1/2) was calculated as 0.693/λz, where λz is the elimination rate constant derived from the terminal slope of the log concentration versus time curve. For participants with predose concentrations below the assay quantitation limit, single-dose AUC from time 0 to infinity was estimated as AUC0–24 plus the C24 divided by λz. Apparent oral clearance (CL/F) was calculated as dose divided by AUC0–24. Concentrations that were below the limit of quantitation of the assay were set at half the lower limit of quantitation to calculate summary statistics. Absorption lags were defined as 1-hour postdose concentrations that were lower than observed predose concentrations. The minimum exposure target for atazanavir was the 10th percentile AUC0–24 in nonpregnant adults with HIV (28.4 μg × h/mL), which was estimated from published pharmacokinetic parameters.[12]

Statistical Analysis

Each woman's atazanavir exposure during pregnancy was determined in real time, compared with AUC0–24 values for nonpregnant adult historical controls, and reported to each participant's care provider. Descriptive statistics were calculated for pharmacokinetic parameters during each study period. Pharmacokinetic parameters during the second trimester versus postpartum and during the third trimester versus postpartum were compared at the within-participant level using the Wilcoxon signed-rank test, with a 2-sided P value ≤0.10 considered statistically significant. Within-participant geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for pharmacokinetic parameters in the pregnant versus nonpregnant conditions were calculated for atazanavir and cobicistat to estimate the range of percentage changes between the 2 conditions consistent with the observed data and to assess clinical importance to inform dosing recommendations. Participants with no data or nonevaluable data in any study period were excluded from the matched comparisons.

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