Pharmacokinetics of metformin during pregnancy.
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ABSTRACT:
SUBMITTER: Eyal S
PROVIDER: S-EPMC2872944 | biostudies-literature | 2010 May
REPOSITORIES: biostudies-literature
Publications
Pharmacokinetics of metformin during pregnancy.
Eyal Sara S Easterling Thomas R TR Carr Darcy D Umans Jason G JG Miodovnik Menachem M Hankins Gary D V GD Clark Shannon M SM Risler Linda L Wang Joanne J Kelly Edward J EJ Shen Danny D DD Hebert Mary F MF
Drug metabolism and disposition: the biological fate of chemicals 20100129 5
Our objective was to evaluate the pharmacokinetics of metformin during pregnancy. Serial blood and urine samples were collected over one steady-state dosing interval in women treated with metformin during early to late pregnancy (n = 35) and postpartum (n = 16). Maternal and umbilical cord blood samples were obtained at delivery from 12 women. Metformin concentrations were also determined in breast milk samples obtained over one dosing interval in 6 women. Metformin renal clearance increased sig ...[more]
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Project description:This study's primary objective was to fully characterize the pharmacokinetics of metformin in pregnant women with gestational diabetes mellitus (GDM) versus nonpregnant controls. Steady-state oral metformin pharmacokinetics in pregnant women with GDM receiving either metformin monotherapy (n = 24) or a combination with glyburide (n = 30) as well as in nonpregnant women with type 2 diabetes mellitus (T2DM) (n = 24) were determined utilizing noncompartmental techniques. Maternal and umbilical cord blood samples were collected at delivery from 38 women. With both 500- and 1000-mg doses, metformin bioavailability, volume of distribution beta (V ? ), clearance, and renal clearance were significantly increased during pregnancy. In addition, in the women receiving metformin 500 mg, significantly higher metformin apparent oral clearance (CL/F) (27%), weight-adjusted renal secretion clearance (64%), and apparent oral volume of distribution beta (V ? /F) (33%) were seen during pregnancy. Creatinine clearance was significantly higher during pregnancy. Increasing metformin dose from 500 to 1000 mg orally twice daily significantly increased V ? /F by 28%, weight-adjusted V ? /F by 32% and CL/F by 25%, and weight-adjusted CL/F by 28% during pregnancy. Mean metformin umbilical cord arterial-to-venous plasma concentration ratio was 1.0 ± 0.1, venous umbilical cord-to-maternal concentration ratio was 1.4 ± 0.5, and arterial umbilical cord-to-maternal concentration ratio was 1.5 ± 0.5. Systemic exposure after a 500-mg dose of metformin was lower during pregnancy compared with the nonpregnant women with T2DM. However, in patients receiving metformin 1000 mg, changes in estimated bioavailability during pregnancy offset the changes in clearance leading to no significant change in CL/F with the higher dose. SIGNIFICANCE STATEMENT: Gestational diabetes mellitus complicates 5%-13% of pregnancies and is often treated with metformin. Pregnant women undergo physiological changes that alter drug disposition. Preliminary data suggest that pregnancy lowers metformin concentrations, potentially affecting efficacy and safety. This study definitively describes pregnancy's effects on metformin pharmacokinetics and expands the mechanistic understanding of pharmacokinetic changes across the dosage range. Here we report the nonlinearity of metformin pharmacokinetics and the increase in bioavailability, clearance, renal clearance, and volume of distribution during pregnancy.
| S-EPMC7076518 | biostudies-literature
Project description:ObjectiveWe evaluated the pharmacokinetics (PK) of raltegravir in HIV-infected women during pregnancy and postpartum.MethodsInternational Maternal Pediatric Adolescent AIDS Clinical Trials 1026s is an ongoing prospective study of antiretroviral PK during pregnancy (NCT00042289). Women receiving 400 mg raltegravir twice daily in combination antiretroviral therapy had intensive steady-state 12-hour PK profiles performed during pregnancy and at 6- to 12-week postpartum. Targets were trough concentration above 0.035 μg/mL, the estimated 10th percentile in nonpregnant historical controls.ResultsMedian raltegravir area under the curve was 6.6 μg·h/mL for second trimester (n = 16), 5.4 μg·h/mL for third trimester (n = 41), and 11.6 μg·h/mL postpartum (n = 38) (P = 0.03 postpartum vs second trimester, P = 0.001 pp vs third trimester). Trough concentrations were above the target in 69%, 80%, and 79% of second trimester, third trimester, and postpartum subjects, respectively, with wide variability (<0.010-0.917 μg/mL), and no significant difference between third trimester and postpartum trough concentrations was detected. The median ratio of cord blood/maternal raltegravir concentrations was 1.5. HIV RNA levels were <400 copies per milliliter in 92% of women at delivery. Adverse events included elevated liver transaminases in 1 woman and vomiting in 1. All infants with known status are HIV uninfected.ConclusionsMedian raltegravir area under the curve was reduced by approximately 50% during pregnancy; trough concentrations were frequently below target both during late pregnancy and postpartum. Raltegravir readily crossed the placenta. High rates of viral suppression at delivery and the lack of a clear relationship between raltegravir concentration and virologic effect in nonpregnant adults suggest that despite the decreased exposure during pregnancy, a higher dose is not necessary.
| S-EPMC4213295 | biostudies-literature
Project description:To evaluate the steady-state pharmacokinetics of prednisone and its metabolite prednisolone in pregnant and lactating female subjects, 19 subjects received prednisone (4-40 mg/day orally) in early (n = 3), mid (n = 9), and late (n = 13) pregnancy as well as postpartum with (n = 2) and without (n = 5) lactation. Serial blood and urine samples were collected over 1 dosing interval. Prednisone and its metabolite, prednisolone, steady-state noncompartmental pharmacokinetic parameters were estimated. During pregnancy, prednisone apparent oral clearance increased with dose (35.1 ± 11.4 L/h with 5 mg, 52.6 ± 5.2 L/h with 10 mg, and 64.3 ± 6.9 L/h with 20 mg, P = .001). Similarly, unbound prednisone apparent oral clearance increased with dose. In addition, prednisolone renal clearance increased with dose (0.3 ± 0.3 L/h with 5 mg, 0.5 ± 0.4 L/h with 10 mg, and 1.3 ± 1.1 L/h with 20 mg, P = .002). Higher prednisone (r = 0.57, P ? .05) and prednisolone (r = 0.75, P ? .05) concentrations led to a higher percentage of unbound drug. Breast-milk/plasma area under the concentration-time curve ratios were 0.5-0.6 for prednisone and 0.02-0.03 for prednisolone. Relative infant doses were 0.35% to 0.53% and 0.09% to 0.18%, for prednisone and prednisolone, respectively. Prednisone and prednisolone exhibit dose- and concentration-dependent pharmacokinetics during pregnancy, and infant exposure to these agents via breast milk is minimal.
| S-EPMC6310475 | biostudies-literature
Project description:The purpose of this study was to evaluate the pharmacokinetics of ritonavir-boosted fosamprenavir during pregnancy and postpartum. Amprenavir (the active moiety of fosamprenavir) and ritonavir intensive pharmacokinetic evaluations were performed at steady state during the second and third trimesters of pregnancy and postpartum. Plasma concentrations of amprenavir and ritonavir were measured using high-performance liquid chromatography. The target amprenavir area under the concentration-versus-time curve (AUC) was higher than the 10th percentile (27.7??g · h/ml) of the median area under the curve for ritonavir-boosted fosamprenavir in adults receiving twice-daily fosamprenavir-ritonavir at 700?mg/100?mg. Twenty-nine women were included in the analysis. The amprenavir AUC from time zero to 12 h (AUC0-12) was lower (geometric mean ratio [GMR], 0.60 [confidence interval {CI}, 0.49 to 0.72] [P?<?0.001]) while its apparent oral clearance was higher (GMR, 1.68 [CI, 1.38 to 2.03] [P?<?0.001]) in the third trimester than postpartum. Similarly, the ritonavir AUC0-12 was lower in the second (GMR, 0.51 [CI, 0.28 to 0.91] [P?=?0.09]) and third (GMR, 0.72 [CI, 0.55 to 0.95] [P?=?0.005]) trimesters than postpartum, while its apparent oral clearance was higher in the second (GMR, 1.98 [CI, 1.10 to 3.56] [P?=?0.06]) and third (GMR, 1.38 [CI, 1.05 to 1.82] [P?=?0.009]) trimesters than postpartum. The amprenavir area under the curve exceeded the target for 6/8 (75%) women in the 2nd trimester, 18/28 (64%) in the 3rd trimester, and 19/22 (86.4%) postpartum, and the trough concentrations (C min) of amprenavir were 4- to 16-fold above the mean amprenavir-protein-adjusted 50% inhibitory concentration (IC50) of 0.146??g/ml. Although amprenavir plasma concentrations in women receiving ritonavir-boosted fosamprenavir were lower during pregnancy than postpartum, the reduced amprenavir concentrations were still above the exposures needed for viral suppression.
| S-EPMC7179299 | biostudies-literature
Project description:The objective of this study was to evaluate the steady-state pharmacokinetics of metoprolol during pregnancy and lactation. Serial plasma, urine, and breast milk concentrations of metoprolol and its metabolite, ?-hydroxymetoprolol, were measured over 1 dosing interval in women treated with metoprolol (25-750?mg/day) during early pregnancy (n?=?4), mid-pregnancy (n?=?14), and late pregnancy (n?=?15), as well as postpartum (n?=?9) with (n?=?4) and without (n?=?5) lactation. Subjects were genotyped for CYP2D6 loss-of-function allelic variants. Using paired analysis, mean metoprolol apparent oral clearance was significantly higher in mid-pregnancy (361?±?223 L/h, n?=?5, P?<?.05) and late pregnancy (568?±?273 L/h, n?=?8, P?<?.05) compared with ?3 months postpartum (200?±?131 and 192?±?98 L/h, respectively). When the comparison was limited to extensive metabolizers (EMs), metoprolol apparent oral clearance was significantly higher during both mid- and late pregnancy (P?<?.05). Relative infant exposure to metoprolol through breast milk was <1.0% of maternal weight-adjusted dose (n?=?3). Because of the large, pregnancy-induced changes in metoprolol pharmacokinetics, if inadequate clinical responses are encountered, clinicians who prescribe metoprolol during pregnancy should be prepared to make aggressive changes in dosage (dose and frequency) or consider using an alternate beta-blocker.
| S-EPMC5564514 | biostudies-literature
Project description:BackgroundLimited data exist on efavirenz pharmacokinetics in HIV-positive pregnant women and neonatal washout.MethodsHIV-infected pregnant women receiving 600 mg efavirenz once daily had intensive steady-state 24-h pharmacokinetics profiles during the second trimester (2T), third trimester (3T) and 6-12 weeks postpartum (PP). Maternal and umbilical cord blood samples were drawn at delivery and neonatal washout pharmacokinetics were determined. Therapeutic targets were the estimated 10th percentile efavirenz area under the concentration-time curve (AUC) in non-pregnant historical controls (40.0 μg•h/ml) and a trough concentration (C24 h) of 1 μg/ml. Data were prospectively collected within two trials: IMPAACT P1026s (United States) and PANNA (Europe).ResultsAmong 42 women studied, 15, 42 and 40 had efavirenz pharmacokinetic data available in 2T, 3T and PP, respectively. Median (range) 3T age 33 (20.7-43.5) years, weight 74 (50-132) kg and gestational age 33.4 (28.4-37.9 weeks). Efavirenz AUC during the 3T (60 μg•h/ml) was similar to that reported in non-pregnant adults (58 μg•h/ml). Exposure in the 2T was lower, but within the 0.80-1.25 range. C24 concentrations during pregnancy were lower compared to historical controls on 600 mg efavirenz, however, they were similar to the C24 concentrations after equally potent dose of 400 mg efavirenz. Cord blood/maternal plasma concentration ratio (range) was 0.67 (0.36-0.95). Among 23 infants with washout data available, median (interquartile range) elimination half-life was 65.6 h (40.6-129). HIV RNA viral loads at delivery were <400 and <50 copies/ml for 96.7% and 86.7% of women, respectively. In 3T and PP, respectively, 8/41 (19%) and 6/40 (15%) had AUC below target; 7/41 (17%) and 3/39 (8%) had C24 below target.ConclusionsEfavirenz exposure was similar during pregnancy compared with PP, C24 was in line with C24 after 400 mg equipotent efavirenz dosing. Efavirenz readily crossed the placenta and infant elimination half-life was over twice that of maternal participants. Clincaltrials.gov identifiers: NCT00825929 and NCT00042289.
| S-EPMC6642905 | biostudies-literature
Project description:BackgroundThis study aims to evaluate the pharmacokinetics of an increased dose of darunavir (800 mg twice daily) with 100 mg ritonavir during pregnancy and postpartum.MethodsDarunavir (DRV) and ritonavir (RTV; r) intensive pharmacokinetic evaluations were performed at steady state during the second and third trimesters of pregnancy (DRV/r 800/100 mg bid) and 2-3 weeks postpartum (DRV/r 600/100 mg twice daily). Plasma concentrations of darunavir and ritonavir were measured using high-performance liquid chromatography. Target darunavir area under the concentration time curve (AUC) was >70% (43.6 μg × h/mL) of median AUC (62.3 μg × h/mL) in nonpregnant adults on twice daily darunavir-ritonavir 600/100 mg.ResultsTwenty-four women were included in the analysis. Darunavir AUC0-12 was lower with the increased dose during the second {[geometric mean ratio (GMR) of 0.62 (IQR 0.44-0.88); P = 0.055]} and third trimesters [GMR 0.64 (IQR 0.55-0.73); P = <0.001] compared with postpartum. Darunavir apparent clearance was higher during the second [GMR 1.77 (IQR 1.24-2.51); P = 0.039] and third trimesters [GMR 2.01 (IQR 1.17-2.35); P = <0.001] compared with postpartum. Similarly, ritonavir AUC0-12 was lower during the third trimester [GMR 0.65 (IQR 0.52-0.82); P = 0.007] compared with postpartum, whereas its apparent clearance was higher during the third trimester [GMR 1.53 (IQR 1.22-1.92); P = 0.008] compared with postpartum. No major drug-related safety concerns were noted.ConclusionsIncreasing darunavir dose to 800 mg BID failed to significantly increase darunavir exposure compared with 600 mg BID. Other strategies, such as increasing the ritonavir dose should be investigated.
| S-EPMC7258985 | biostudies-literature
Project description:BackgroundFew data are available describing atazanavir exposure during pregnancy, especially when used in combination with tenofovir, whose coadministration with atazanavir results in decreased atazanavir exposure.DesignInternational Maternal Pediatric Adolescent AIDS Clinical Trials 1026 s is an ongoing, prospective, nonblinded study of antiretroviral pharmacokinetics in HIV-infected pregnant women that included 2 cohorts receiving atazanavir/ritonavir 300 mg/100 mg once daily, either with or without tenofovir.MethodsIntensive steady-state 24-hour pharmacokinetic profiles were performed during the third trimester and at 6-12 weeks postpartum. Atazanavir was measured by reverse-phase high-performance liquid chromatography (detection limit 0.047 mcg/mL). Pharmacokinetic targets were the estimated 10th percentile atazanavir area under the concentration versus time curve [(AUC): 29.4 mcg · hr · mL-1] in nonpregnant historical controls (mean AUC = 57 mcg · hr · mL-1) and a trough concentration of 0.15 mcg/mL, the concentration target used in therapeutic drug monitoring programs.ResultsMedian atazanavir AUC was reduced during the third trimester compared with postpartum for subjects not receiving tenofovir (41.9 vs. 57.9 mcg · hr · mL-1, P = 0.02) and for subjects receiving tenofovir (28.8 vs. 39.6 mcg · hr · mL-1, P = 0.04). During the third trimester, AUC was below the target in 33% (6 of 18) of women not receiving tenofovir and 55% (11 of 20) of women receiving tenofovir. Trough concentration was below the target in 6% (1 of 18) of women not receiving tenofovir and 15% (3 of 20) of women receiving tenofovir. The median (range) ratio of cord blood/maternal atazanavir concentration in 29-paired samples was 0.18 (0-0.45).ConclusionsAtazanavir exposure is reduced by pregnancy and by concomitant tenofovir use. A dose increase of atazanavir/ritonavir to 400 mg/100 mg may be necessary in pregnant women to ensure atazanavir exposure equivalent to that seen in nonpregnant adults.
| S-EPMC3125419 | biostudies-literature
Project description:The broad-based legalization of cannabis use has created a strong need to understand its impact on human health and behavior. The risks that may be associated with cannabis use, particularly for sensitive subgroups such as pregnant women, are difficult to define because of a paucity of dose-response data and the recent increase in cannabis potency. Although there is a large body of evidence detailing the mode of action of ?9-tetrahydrocannabinol (THC) in adults, little work has focused on understanding how cannabis use during pregnancy may impact the development of the fetal nervous system and whether additional plant-derived cannabinoids might participate. This manuscript presents an overview of the historical and contemporary literature focused on the mode of action of THC in the developing brain, comparative pharmacokinetics in both pregnant and nonpregnant model systems and neurodevelopmental outcomes in exposed offspring. Despite growing public health significance, pharmacokinetic studies of THC have focused on nonpregnant adult subjects and there are few published reports on disposition parameters during pregnancy. Data from preclinical species show that THC readily crosses the placenta although fetal exposures appear lower than maternal exposures. The neurodevelopmental data in humans and animals suggest that prenatal exposure to THC may lead to subtle, persistent changes in targeted aspects of higher-level cognition and psychological well-being. There is an urgent need for well-controlled studies in humans and preclinical models on THC as a developmental neurotoxicant. Until more information is available, pregnant women should not assume that using cannabis during pregnancy is safe.
| S-EPMC6211194 | biostudies-other
Project description:Pregnant women are usually excluded from clinical trials. Physiologically based pharmacokinetic (PBPK) modelling may provide a method to predict pharmacokinetics in pregnant women, without the need to perform extensive in vivo clinical trials. Here, we used mechanistic modelling to delineate the potential impact of drug transporters on darunavir pharmacokinetics and to identify current knowledge gaps that limit accurate PBPK modelling of darunavir/ritonavir (darunavir/r) exposure in pregnancy. Simcyp (version 13.2) was used for PBPK modelling, using physicochemical and in vitro pharmacokinetic parameters of darunavir and ritonavir from the literature. The Michaelis-Menten constant (K m) and the maximum rate of metabolite formation (V max) for cytochrome P450 3A4-mediated darunavir biotransformation and inhibition by ritonavir were determined experimentally, while the contributions of hepatocyte influx and efflux transporters were assessed by sensitivity analysis. The simulations were compared with previously published clinical pharmacokinetic data. We found that use of a well-stirred liver model overestimated darunavir exposure substantially. A permeability-limited liver model, including hepatic uptake and efflux transporters and an efficient enterohepatic circulation step, resulted in an acceptable description of darunavir/r exposure. For the 600/100 mg darunavir/r twice-daily dose and the 800/100 mg once-daily dose, the estimated pharmacokinetic parameters were within a 2-fold range of the reported data. The predicted decreases in the area under the concentration-time curve (AUC) values during pregnancy for the twice- and once-daily doses were 27 and 41%, respectively, which were in line with the observed decreases of 17-22 and 33%. In conclusion, our data support a clinically relevant role of hepatic transporters in darunavir pharmacokinetics. By including them in our model, we successfully approximated the increase in darunavir exposure mediated by ritonavir co-administration and the decrease in darunavir exposure observed during pregnancy.
| S-EPMC4761019 | biostudies-literature