Characterization of Plasma Protein Alterations in Pregnant and Postpartum Individuals Living With HIV to Support Physiologically-Based Pharmacokinetic Model Development

Abstract

Background: Alterations in plasma protein concentrations in pregnant and postpartum individuals can influence antiretroviral (ARV) pharmacokinetics. Physiologically-based pharmacokinetic (PBPK) models can serve to inform drug dosing decisions in understudied populations. However, development of such models requires quantitative physiological information (e.g., changes in plasma protein concentration) from the population of interest.Objective: To quantitatively describe the time-course of albumin and α1-acid glycoprotein (AAG) concentrations in pregnant and postpartum women living with HIV.Methods: Serum and plasma protein concentrations procured from the International Maternal Pediatric Adolescent AIDS Clinical Trial Protocol 1026s (P1026s) were analyzed using a generalized additive modeling approach. Separate non-parametric smoothing splines were fit to albumin and AAG concentrations as functions of gestational age or postpartum duration.Results: The analysis included 871 and 757 serum albumin concentrations collected from 380 pregnant (~20 to 42 wks gestation) and 354 postpartum (0 to 46 wks postpartum) women, respectively. Thirty-six and 32 plasma AAG concentrations from 31 pregnant (~24 to 38 wks gestation) and 30 postpartum women (~2–13 wks postpartum), respectively, were available for analysis. Estimated mean albumin concentrations remained stable from 20 wks gestation to term (33.4 to 34.3 g/L); whereas, concentrations rapidly increased postpartum until stabilizing at ~42.3 g/L 15 wk after delivery. Estimated AAG concentrations slightly decreased from 24 wks gestation to term (53.6 and 44.9 mg/dL) while postpartum levels were elevated at two wks after delivery (126.1 mg/dL) and subsequently declined thereafter. Computational functions were developed to quantitatively communicate study results in a form that can be readily utilized for PBPK model development.Conclusion: By characterizing the trajectory of plasma protein concentrations in pregnant and postpartum women living with HIV, our analysis can increase confidence in PBPK model predictions for HIV antiretrovirals and better inform drug dosing decisions in this understudied population.

Translating Clinical Pharmacology Data in Pregnancy to Evidence‐Based Guideline Recommendations: Perspectives From the HIV Field

“…In an analysis of 871 albumin concentrations from 380 pregnant women with HIV (20-42 weeks' gestation), albumin was on average lower than reference ranges for pregnant people without HIV. 18 This finding has been observed in other studies. 19,20 Separately, in a study that evaluated the PK of lopinavir/ritonavir and efavirenz in Uganda, pregnancy and food insecurity-a marker of malnourishment-were associated with lower drug exposures.…”

“…Demographic and socioeconomic differences between pregnant populations may also be associated with differences in the trajectory and magnitude of PK‐relevant physiological changes. In an analysis of 871 albumin concentrations from 380 pregnant women with HIV (20‐42 weeks’ gestation), albumin was on average lower than reference ranges for pregnant people without HIV 18 . This finding has been observed in other studies 19,20 .…”

“…For highly protein-bound drugs, it may be important to examine free drug concentrations because pregnancy is associated with decreased plasma protein concentrations that can affect the amount of the free, pharmacologically active drug available at target sites. 18 Small-molecule drugs often bind to plasma proteins such as albumin and/or α 1 -acid glycoprotein or to cellular components including erythrocytes. During pregnancy, albumin and α 1 -acid glycoprotein concentrations in plasma decrease significantly in part due to increases in plasma volume and increased urinary protein excretion.…”

Pharmacokinetics of Antiretroviral Agents in Pregnant Individuals Living With HIV: Current Status and Considerations for Study Design and Interpretation

“…Recently, a quantitative description of the time course of albumin and AAG concentrations in pregnant and postpartum women living with HIV was published. 33 A change in plasma protein concentrations can alter the PK of highly protein-bound ARVs. [5][6][7] Decreased concentrations of plasma proteins can lead to increased concentrations of free drug, which is the pharmacologically active form and the only fraction that can be metabolized by hepatic enzymes.…”

“…The 2 main plasma proteins, albumin and AAG, are decreased during pregnancy primarily due to dilution effects. Recently, a quantitative description of the time course of albumin and AAG concentrations in pregnant and postpartum women living with HIV was published 33 …”