Objectives
Tenofovir disoproxil fumarate (TDF) is increasingly used in the highly active antiretroviral therapy (HAART) regimens of pregnant women, but limited data exist on the pregnancy ...pharmacokinetics of chronically dosed TDF. This study described tenofovir pharmacokinetics during pregnancy and postpartum.
Methods
International Maternal Pediatric and Adolescent AIDS Clinical Trials (IMPAACT) P1026s is a prospective, nonblinded pharmacokinetic study of HIV‐infected pregnant women that included a cohort receiving 300 mg TDF once daily. Steady‐state 24‐hour pharmacokinetic profiles were measured at the second and third trimesters, postpartum, and in maternal and umbilical cord samples collected at delivery. Tenofovir was measured by liquid chromatography−mass spectrometry (LC‐MS). The target area under the concentration versus time curve from time 0 to 24 h post dose (AUC) was ≥ 1.99 μg h/mL (nonpregnant historical control 10th percentile).
Results
The median tenofovir AUC was decreased during the second (1.9 μg h/mL) and third (2.4 μg h/mL; P = 0.005) trimesters versus postpartum (3.0 μg h/mL). Tenofovir AUC exceeded the target for two of four women (50%) in the second trimester, 27 of 37 women 73%; 95% confidence interval (CI) 56%, 86% in the third trimester, and 27 of 32 women (84%; 95% CI 67%, 95%) postpartum (P > 0.05). Median second/third‐trimester troughs were lower (39/54 ng/mL) than postpartum (61 ng/mL). Median third‐trimester weight was greater for subjects below the target AUC versus those above the target (97.9 versus 74.2 kg, respectively; P = 0.006). The median ratio of cord blood to maternal concentrations was 0.88. No infants were HIV infected.
Conclusions
This study found lower tenofovir AUC and troughs during pregnancy. Transplacental passage with chronic TDF use during pregnancy was high. Standard TDF doses appear to be appropriate for most HIV‐infected pregnant women but therapeutic drug monitoring with dose adjustment should be considered in pregnant women with high weight (> 90 kg) or inadequate HIV RNA response.
Background and Purpose: Ziconotide is a peptide that blocks N‐type calcium channels and is antihyperalgesic after intrathecal (IT) delivery. We here characterize the spinal kinetics of IT bolus and ...infused ziconotide in dog.
Experimental Approach: Male beagle dogs (N= 5) were prepared with chronic IT lumbar injection and cerebrospinal fluid (LCSF) sampling catheters connected to vest‐mounted pumps. Each dog received the following: 1) IT bolus ziconotide (10 µg + 1 µCi 3H‐inulin); 2) IT infusion for 48 hours of ziconotide (1 µg/100 µL/hour); 3) IT infusion for 48 hours of ziconotide (5 µg/100 µL/hour); and 4) intravenous injection of ziconotide (0.1 mg/kg). After IT bolus, LCSF ziconotide and inulin showed an initial peak and biphasic (distribution/elimination) clearance (ziconotide T1/2‐α/β= 0.14 and 1.77 hours, and inulin T1/2‐α/β= 0.16 and 3.88 hours, respectively). The LCSF : plasma ziconotide concentration ratio was 20,000:1 at 30 min and 30:1 at eight hours. IT infusion of 1 and then 5 µg/hour resulted in LCSF concentrations that peaked by eight hours and remained stable at 343 and 1380 ng/mL, respectively, to the end of the 48‐hour infusions. Terminal elimination T1/2 after termination of continuous infusion was 2.47 hours. Ziconotide LCSF : cisternal CSF : plasma concentration ratios after infusion of 1 and 5 µg/hour were 1:0.017:0.001 and 1:0.015:0.003, respectively. IT infusion of ziconotide at 1 µg/hour inhibited thermal skin twitch by 24 hours and produced modest trembling, ataxia, and decreased arousal. Effects continued through the 48‐hour infusion period, increased in magnitude during the subsequent 5 µg/hour infusion periods, and disappeared after drug clearance.
Conclusions and Implications: After IT bolus or infusion, ziconotide displays linear kinetics that are consistent with a hydrophilic molecule of approximately 2500 Da that is cleared slightly more rapidly than inulin from the LCSF. Behavioral effects were dose dependent and reversible.
Naltrexone is effective in treating opioid dependence by blocking µ, κ and δ opiate receptors. Naltrexone is mainly metabolized to an active metabolite 6β-naltrexol by dihydrodiol dehydrogenase ...enzymes. Concomitant opioids will not be effective while patients are taking this antagonist. This was a retrospective analysis of urinary excretion data collected from patients being treated with pain between November 2011 and May 2012. Naltrexone, 6β-naltrexol and concomitant opiate concentrations were measured by liquid chromatography-tandem mass spectrometry. Interpatient variability was calculated from first-visit specimens, and intrapatient variability was calculated from patients with two or more visits. Relationships of the metabolic ratio (MR; 6β-naltrexol/naltrexone) with age, gender and urinary pH were also explored. From 88 first-visit patient specimens, the median MR was 3.28 (range 0.73-17.42). The MR was higher in women than men (5.00 vs. 3.14, P< 0.05). The MR showed no association based on age and urinary pH. Eighteen of 88 patients taking oral naltrexone tested positive for concomitant opiate use. Urinary MRs of 6β-naltrexol/naltrexone were highly variable, which may contribute to variability in efficacy, toxicity and patient willingness to take naltrexone as directed. Twenty percent of patients tested positive for opiates and naltrexone, thus showing the importance of monitoring patients taking naltrexone.
Objectives
The aim of the study was to describe emtricitabine pharmacokinetics during pregnancy and postpartum.
Methods
The International Maternal Pediatric and Adolescent AIDS Clinical Trials ...(IMPAACT), formerly Pediatric AIDS Clinical Trials Group (PACTG), study P1026s is a prospective pharmacokinetic study of HIV‐infected pregnant women taking antiretrovirals for clinical indications, including a cohort taking emtricitabine 200 mg once daily. Intensive steady‐state 24‐hour emtricitabine pharmacokinetic profiles were performed during the third trimester and 6–12 weeks postpartum, and on maternal and umbilical cord blood samples collected at delivery. Emtricitabine was measured by liquid chromatography–mass spectrometry with a quantification limit of 0.0118 mg/L. The target emtricitabine area under the concentration versus time curve, from time 0 to 24 hours post dose (AUC0‐24), was ≥7 mg h/L (≤30% reduction from the typical AUC of 10 mg h/L in nonpregnant historical controls). Third‐trimester and postpartum pharmacokinetics were compared within subjects.
Results
Twenty‐six women had pharmacokinetics assessed during the third trimester (median 35 weeks of gestation) and 22 postpartum (median 8 weeks postpartum). Mean 90% confidence interval (CI) emtricitabine pharmacokinetic parameters during the third trimester vs. postpartum were, respectively: AUC: 8.0 (7.1–8.9) vs. 9.7 (8.6–10.9) mg h/L (P = 0.072); apparent clearance (CL/F): 25.0 (22.6–28.3) vs. 20.6 (18.4–23.2) L/h (P = 0.025); 24 hour post dose concentration (C24): 0.058 (0.037–0.063) vs. 0.085 (0.070–0.010) mg/L (P = 0.006). The mean cord:maternal ratio was 1.2 (90% CI 1.0–1.5). The viral load was <400 HIV‐1 RNA copies/mL in 24 of 26 women in the third trimester, in 24 of 26 at delivery, and in 15 of 19 postpartum. Within‐subject comparisons demonstrated significantly higher CL/F and significantly lower C24 during pregnancy; however, the C24 was well above the inhibitory concentration 50%, or drug concentration that suppresses viral replication by half (IC50) in all subjects.
Conclusions
While we found higher emtricitabine CL/F and lower C24 and AUC during pregnancy compared with postpartum, these changes were not sufficiently large to warrant dose adjustment during pregnancy. Umbilical cord blood concentrations were similar to maternal concentrations.
Objectives
Pregnancy results in physiological changes altering the pharmacokinetics of drugs metabolized by cytochrome P450 3A4 (CYP3A4). The urinary ratio of 6‐β hydroxycortisol to cortisol (6βHF : ...F) is a marker of CYP3A4 induction. We sought to evaluate its change in antiretroviral (ARV)‐treated HIV‐1‐infected women and to relate this change to ARV pharmacokinetics.
Methods
Women receiving various ARVs had pharmacokinetic evaluations during the third trimester of pregnancy (> 30 weeks) and postpartum with determination of 6βHF : F carried out on the same days. The Wilcoxon signed rank test was used to compare the ratio antepartum to postpartum. The relationship between the change in ratio and the change in pharmacokinetics was analysed using Kendall's tau.
Results
6βHF : F ratios were available for 107 women antepartum, with 54 having postpartum values. The ratio was higher antepartum (P = 0.033) (median comparison 1.35; 95% confidence interval 1.01, 1.81). For 71 women taking a protease inhibitor (PI), the antepartum vs. postpartum 6βHF : F comparison was marginally significant (P = 0.058). When the change in the 6βHF : F ratio was related to the change in the dose‐adjusted ARV area under the plasma concentration vs. time curve (AUC) between antepartum and postpartum, the 35 subjects in the lopinavir/ritonavir (LPV/r) arms demonstrated an inverse relationship (P = 0.125), albeit this correlation did not reach statistical significance.
Conclusions
A 35% increase in the urinary 6βHF : F ratio was measured during late pregnancy compared with postpartum, indicating that CYP3A induction occurs during pregnancy. The trend towards an inverse relationship between the change in the 6βHF : F ratio and the change in the LPV AUC antepartum vs. postpartum suggests that CYP3A induction may be one mechanism behind altered LPV exposure during pregnancy.
Background
Pregnancy may alter protein binding (PB) of highly bound protease inhibitors due to changes in plasma concentrations of albumin and α‐1 acid glycoprotein (AAG). Small changes in PB can ...greatly impact the fraction of drug unbound (FU) exerting pharmacological effect. We report lopinavir (LPV) PB during third trimester (antepartum, AP) compared to ≥1.7 weeks postpartum (PP) to determine if FU changes compensate for reduced total concentrations reported previously.
Methods
P1026s enrolled women receiving LPV/ritonavir, soft gel capsules 400/100 mg or 533/133 mg twice daily. LPV FU, albumin and AAG were determined AP and PP.
Results
AP/PP samples were available from 29/25 women respectively with all but one woman receiving the same dose AP/PP. LPV FU was increased 18% AP vs. PP (mean 0.96±0.16% AP vs. 0.82±0.21% PP, P=0.001). Mean protein concentrations were reduced AP (AAG=477 mg/L; albumin=3.28 mg/dL) vs. PP (AAG=1007 mg/L; albumin=3.85 mg/dL) (P<0.0001 for each comparison). AAG concentration correlated with LPV binding. Total LPV concentration did not correlate with LPV FU AP or PP. However, higher LPV concentration PP was associated with reduced PB and higher FU after adjustment for AAG.
Conclusions
LPV FU was higher and AAG lower AP vs. PP. The 18% increase in LPV FU AP is smaller than the reduction in total LPV concentration reported previously and is not of sufficient magnitude to eliminate the need for an increased dose during pregnancy.
Objectives
Pregnancy results in physiological changes altering the pharmacokinetics of drugs metabolized by cytochrome
P
450 3
A
4 (
CYP3A4
). The urinary ratio of 6‐β hydroxycortisol to cortisol (
...6βHF
:
F
) is a marker of
CYP3A4
induction. We sought to evaluate its change in antiretroviral (
ARV
)‐treated
HIV
‐1‐infected women and to relate this change to
ARV
pharmacokinetics.
Methods
Women receiving various
ARVs
had pharmacokinetic evaluations during the third trimester of pregnancy (> 30 weeks) and postpartum with determination of 6β
HF
:
F
carried out on the same days. The
W
ilcoxon signed rank test was used to compare the ratio antepartum to postpartum. The relationship between the change in ratio and the change in pharmacokinetics was analysed using
K
endall's tau.
Results
6βHF :
F
ratios were available for 107 women antepartum, with 54 having postpartum values. The ratio was higher antepartum (
P
= 0.033) (median comparison 1.35; 95% confidence interval 1.01, 1.81). For 71 women taking a protease inhibitor (PI), the antepartum
vs.
postpartum 6β
HF
:
F
comparison was marginally significant (
P
= 0.058). When the change in the 6β
HF
:
F
ratio was related to the change in the dose‐adjusted ARV area under the plasma concentration
vs.
time curve (
AUC
) between antepartum and postpartum, the 35 subjects in the lopinavir/ritonavir (
LPV
/r) arms demonstrated an inverse relationship (
P
= 0.125), albeit this correlation did not reach statistical significance.
Conclusions
A 35% increase in the urinary 6β
HF
:
F
ratio was measured during late pregnancy compared with postpartum, indicating that
CYP3A
induction occurs during pregnancy. The trend towards an inverse relationship between the change in the 6β
HF
:
F
ratio and the change in the
LPV AUC
antepartum
vs.
postpartum suggests that
CYP3A
induction may be one mechanism behind altered
LPV
exposure during pregnancy.
Objective
Tricyclic antidepressants (TCAs) are first‐line treatment for neuropathic pain. Despite widespread use, many health care providers do not know which patients are currently taking TCAs. The ...objective of this retrospective data analysis was to determine adherence rates to amitriptyline, nortriptyline, or imipramine. The rate at which patients used TCAs (confirmed by presence of TCA in the urine) but did not inform their health care provider is also reported (non‐informed prescriber rate). Finally, the effects of age, sex, and number of prescriptions on adherence and non‐informed prescriber rates were assessed.
Methods
Urinary excretion data were obtained from 55,296 patients with pain and were analyzed using liquid chromatography tandem mass spectrometry in a multiplex assay which included amitriptyline, nortriptyline, and imipramine.
Results
The adherence rate was 66% (1,407/2,137); the rate of non‐informed prescribers was 3% (1,547/55,296) among the general population, and 52% (1,547/2,954) when only TCA users were considered. While adherence was higher among older and female subjects, the number of other medications did not affect adherence rate.
Conclusions
This analysis reveals that many prescribers are not informed when patients start and stop using TCAs.
This study examined zolpidem and concurrent opioid, benzodiazepine, other central nervous system (CNS) depressants, and alcohol use. Urine specimens were analyzed using liquid chromatography–mass ...spectrometry (LC–MS/MS). Specimens were tested for zolpidem (n = 71,919) and separated into a provider-reported medication list documenting (n = 5,257) or not documenting zolpidem use (n = 66,662). Zolpidem-positive specimens were further separated into reported and unreported use cohorts. The total number of zolpidem-positive specimens in the reported and unreported use cohorts was 3,391 and 3,190, respectively. Non-informed prescribers were 4.4% (3,190/71,919) among the general population and 48.5% (3,190/6,581) when only zolpidem users were considered. In the zolpidem user population, the most common concurrent opioids in both cohorts were hydrocodone and oxycodone. Alprazolam and clonazepam were higher in the unreported use cohort (P ≤ 0.05). The unreported use cohort also had a higher detection of zolpidem plus a benzodiazepine (49.7 vs. 46%; P ≤ 0.05), zolpidem plus an opioid and a benzodiazepine (40.8% vs. 37.4%; P ≤ 0.05) and zolpidem plus an opioid, a benzodiazepine, and an other CNS depressant (12.9 vs. 10.9%; P ≤ 0.05). Concurrent use of zolpidem, an opioid, a benzodiazepine and an other CNS depressant is prevalent in a pain patient population.
To describe abacavir pharmacokinetics during pregnancy and postpartum; physiological changes during pregnancy are known to affect antiretroviral drug disposition.
The Pediatric AIDS Clinical Trials ...Group P1026s study is an on-going, prospective, non-blinded pharmacokinetic study of pregnant women receiving one or more antiretroviral drugs for routine clinical care, including a cohort receiving abacavir 300 mg twice daily.
Serial plasma samples (predose, 1, 2, 4, and 6 h postdose) obtained antepartum (30-36 weeks of gestation) and again postpartum (6-12 weeks after delivery) were assayed for abacavir concentration by reversed-phase high-performance liquid chromatography.
Antepartum evaluations were available for 25 women mean age, 28.6 years (SD, 6); mean third-trimester weight 92 kg (SD, 35.4); and race/ethnicity 52% black, 28% Hispanic, 16% white, 4% Asian, with geometric mean abacavir area under the concentration-time curve (AUC) of 5.9 mg.h/l 90% confidence interval (CI), 5.2-6.8 and maximum plasma concentration (Cmax) of 1.9 mg/l (90% CI, 1.6-2.2). Seventeen women completed postpartum sampling, and the ratios of antepartum to postpartum AUC and Cmax were 1.04 (90% CI, 0.91-1.18) and 0.79 (90% CI, 0.65-0.98), respectively.
Abacavir AUC during pregnancy was similar to that at 6-12 weeks postpartum and to that for non-pregnant historical controls (5.8 mg.h/l). Consequently, pregnancy does not appear to affect overall abacavir exposure significantly or to necessitate dose adjustments.
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