Alteration in cytochrome P450 3A4 activity as measured by a urine cortisol assay in HIV-1-infected pregnant women and relationship to antiretroviral pharmacokinetics.

OBJECTIVES: Pregnancy results in physiological changes altering the pharmacokinetics of drugs metabolized by cytochrome P450 3A4 (CYP3A4). The urinary ratio of 6-ß hydroxycortisol to cortisol (6ßHF : 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 6ßHF : 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: 6ßHF : 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 6ßHF : F comparison was marginally significant (P=0.058). When the change in the 6ßHF : 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 6ßHF : 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 6ßHF : 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.

Pharmacokinetics of tenofovir during pregnancy and postpartum.

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.

Effect of pregnancy on emtricitabine pharmacokinetics.

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 (AUC(0-24) ), 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 (C(24) ): 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 C(24) during pregnancy; however, the C(24) was well above the inhibitory concentration 50%, or drug concentration that suppresses viral replication by half (IC(50) ) in all subjects. CONCLUSIONS: While we found higher emtricitabine CL/F and lower C(24) 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.

Lopinavir protein binding in HIV-1-infected pregnant women.

BACKGROUND: Pregnancy may alter protein binding (PB) of highly bound protease inhibitors due to changes in plasma concentrations of albumin and alpha-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 > or =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.

Pharmacokinetics of new 625 mg nelfinavir formulation during pregnancy and postpartum.

OBJECTIVES: Our objective was to evaluate the pharmacokinetics of nelfinavir (NFV) (625 mg tablets) 1250 mg twice daily during pregnancy and postpartum. METHODS: The participants were HIV-1-infected pregnant women enrolled in P1026s and receiving NFV (625 mg tablets) 1250 mg twice daily as part of routine clinical care. Intensive steady-state 12-h NFV pharmacokinetic profiles were performed during pregnancy and postpartum. The target NFV area under the plasma concentration-time curve (AUC(0-12)) was >or=10th percentile NFV AUC(0-12) in non-pregnant historical controls (18.5 microg h/mL). RESULTS: Of 27 patients receiving NFV, pharmacokinetic data were available for four (second trimester), 27 (third trimester) and 22 (postpartum) patients. The NFV maximum concentration (C(max)), 12-h post-dose concentration (C(12)) and AUC(0-12) were significantly lower during the third trimester compared to postpartum (P

Pharmacokinetics and safety of nelfinavir when used in combination with zidovudine and lamivudine in HIV-infected pregnant women: Pediatric AIDS Clinical Trials Group (PACTG) Protocol 353.

BACKGROUND: Combination antiretroviral regimens including nelfinavir (NFV) are commonly used in pregnancy. We studied the safety, antiviral effect, and pharmacokinetics of NFV and its M8 metabolite with two dosing regimens in combination with zidovudine (ZDV) and lamivudine (3TC) in HIV-infected pregnant women. METHOD: HIV-infected pregnant women between 14 and 34 weeks gestation received NFV (Cohort 1: 750 mg tid, n = 10; Cohort 2: 1250 mg bid, n = 23) with ZDV and 3TC. Serial blood sampling for NFV concentrations was performed antepartum (AP) and 6 weeks postpartum (PP). Maternal and cord blood samples were also obtained at delivery. NFV and M8 levels were determined by high-performance liquid chromatography. The pharmacokinetic (PK) target was an extrapolated NFV AUC0-24 > 30 mug . h/mL. Mothers were followed frequently for potential clinical and laboratory toxicity. RESULTS: Overall, NFV in combination with ZDV and 3TC was well tolerated. The PK target was met in 3/8 AP and 5/7 PP in Cohort 1 and 17/21 AP and 16/17 PP in Cohort 2. When Cohort 2 NFV PK parameters AP and PP were compared, median Cmax (3.90 microg/mL vs. 5.01 microg/mL, p < .05) and AUC0-24 (56.6 vs. 86.8 microg . h/mL, p < .05) were increased PP and oral clearance (Cl/F; 44.2 vs. 28.8 L/h, p < .05) was decreased PP. The average M8/NFV ratio was increased PP compared to AP (0.085 vs. 0.29, p < .001). Placental transfer of NFV was low with a median cord blood:maternal plasma ratio at delivery of 0.05. Maternal mean CD4+ T cell counts increased significantly and plasma HIV-1 RNA levels decreased from entry to delivery and 6 to 12 weeks postpartum. CONCLUSION: NFV used in combination with ZDV and 3TC was well tolerated in pregnant HIV-infected women and produced a significant improvement in HIV disease parameters. NFV drug exposure is inadequate in most pregnant women receiving 750 mg tid but is much improved with 1250 mg bid. NFV crosses the placenta poorly. The AP increase in NFV oral clearance and decrease in M8/NFV ratio suggest that CYP3A activity increases relative to CYP2C19 activity during pregnancy.

Identification of the K103N resistance mutation in Ugandan women receiving nevirapine to prevent HIV-1 vertical transmission.

OBJECTIVE: A recent trial in Uganda demonstrated that a simple, inexpensive regimen of nevirapine (NVP) prophylaxis can dramatically reduce HIV-1 vertical transmission risk. In this regimen, women receive a single dose of NVP at the onset of labor and infants receive a single dose of NVP within 72 h of birth. The objective of this study was to determine whether HIV-1 variants with NVP resistance mutations were selected in Ugandan women who received this regimen in the Phase I/II trial HIVNET 006. METHODS: Reverse transcriptase (RT) sequences from plasma HIV-1 were analyzed from 15 women 6 weeks after NVP dosing. RT sequences from plasma collected prior to NVP dosing were also analyzed. RESULTS: The K103N NVP resistance mutation was detected 6 weeks after NVP administration in three (20%) out of 15 women (95% confidence interval, 0-40%). Pre-dose samples were available from two of the three women; both pre-dose samples lacked the mutation. Other NVP resistance mutations were absent from all 15 women. Women with the K103N mutation had a longer median NVP elimination half-life, decreased median oral clearance, and increased median area under the concentration time curve than those without the mutation. An evaluable sample was obtained from one of these three women 33 months after delivery; the K103N mutation was not detected in that sample. CONCLUSIONS: This preliminary study demonstrates that HIV-1 with the RT K103N mutation can be detected in some Ugandan women following a single dose of NVP. This suggests that non-nucleoside RT inhibitor resistance may be selected in some people by single dose NVP prophylaxis. Pharmacokinetic data suggested that a more prolonged exposure to NVP after dosing may favor selection of NVP-resistant HIV-1.

Selection and fading of resistance mutations in women and infants receiving nevirapine to prevent HIV-1 vertical transmission (HIVNET 012).

OBJECTIVE: To examine the emergence and fading of NVP resistance (NVP(R)) mutations in HIV-1-infected Ugandan women and infants who received single dose NVP to prevent HIV-1 vertical transmission. DESIGN: We examined NVP(R) in women and infants who received NVP in the HIVNET 012 clinical trial, including 41 out of 48 women with infected infants, 70 randomly-selected women with uninfected infants, and 33 out of 49 infected infants. METHODS: Plasma HIV-1 was analyzed using the Applied Biosystems ViroSeq HIV-1 Genotyping System. RESULTS: NVP(R) mutations were detected in 21 out of 111 (19%) women tested 6-8 weeks after delivery. The rate of NVP(R) was similar among women whose infants were or were not HIV-1 infected. K103N was the most common mutation detected. NVP(R) mutations faded from detection within 12-24 months in all 11 evaluable women. High baseline viral load and low baseline CD4 cell count were associated with development of NVP(R). NVP(R) mutations were detected in 11 out of 24 (46%) evaluable infants who were infected by 6-8 weeks of age. The most common NVP(R) mutation detected in infants was Y181C. Those mutations faded from detection by 12 months of age in all seven evaluable infants. Of nine evaluable infants with late HIV-1 infection, only one had evidence of NVP(R). CONCLUSIONS: NVP(R) was detected more frequently in infants than women following NVP prophylaxis, and different patterns of NVP(R) mutations were detected in women versus infants. NVP(R) was detected infrequently in infants with late HIV-1 infection. NVP-resistant HIV-1 faded from detection in women and infants over time.

A phase I/II study of the safety and pharmacokinetics of nevirapine in HIV-1-infected pregnant Ugandan women and their neonates (HIVNET 006).

OBJECTIVE: To determine the safety, pharmacokinetics, tolerance, antiretroviral activity, and infant HIV infection status after giving a single dose of nevirapine to HIV-1-infected pregnant women during labor and their newborns during the first week of life. DESIGN: An open label phase I/II study. SETTING: Tertiary care hospital, Kampala, Uganda. PATIENTS AND INTERVENTIONS: Nevirapine, 200 mg, was given as a single dose during labor to 21 HIV-1-infected pregnant Ugandan women. In cohort 1, eight infants did not receive nevirapine whereas in cohort 2, 13 infants received a single dose of nevirapine, 2 mg/kg, at 72 h of age. OUTCOMES: The number and type of adverse events; nevirapine concentrations in the plasma and breast milk; maternal plasma HIV-1 RNA copy number before and up to 6 weeks after delivery; and HIV-1 infection status of the infants were monitored. RESULTS: Nevirapine was well tolerated by women and infants; no serious adverse events that were related to nevirapine were observed. Median nevirapine concentration in the women at delivery was 1623 ng/ml (range 238-2356 ng/ml); median cord/maternal blood ratio of 0.75 (0.37-0.93). The median half-life in women was 61.3 h (27-90 h) and the transplacental nevirapine half-life in infants who did not receive a neonatal dose was 54 h. The median half-life after a single dose at 72 h in infants was 46.5 h. During the first week of life, the median colostrum/breast milk to maternal plasma nevirapine concentration was 60.5% (25-122%). The median nevirapine concentration in breast milk 1 week after delivery was 103 ng/ml (25-309 ng/ml). Plasma nevirapine concentrations were above 100 ng/ml in all infants from both cohorts tested at age 7 days. Maternal HIV-1 RNA levels decreased by a median of 1.3 logs at 1 week postpartum, and returned to baseline by 6 weeks postpartum. Detectable plasma HIV-1 RNA was observed in one out of 22 (4.5%) infants at birth; three out of 21 (14%) at 6 weeks; and four out of 21 (19%) at 6 months of age. CONCLUSION: The administration of a single dose of nevirapine to women during labor and to their newborns at 72 h was well tolerated and showed potent antiretroviral activity in the women at 1 week after dosing without rebound above baseline 6 weeks after a single dose. The nevirapine concentration was maintained above the target of 100 ng/ml in infants at age 7 days, even in those infants not receiving a neonatal dose. This regimen has promise as prophylaxis against intrapartum and early breast milk transmission in a breastfeeding population.

Pharmacokinetics of zidovudine in infants: a population analysis across studies.

BACKGROUND: Although the use of zidovudine in newborns and infants has become standard therapy for prophylaxis and therapy of human immunodeficiency virus infection, the developmental pharmacology of zidovudine in the first months of life has not been fully described. METHODS: We used population analysis to estimate zidovudine pharmacokinetic parameters in newborns and infants who either participated in one of five Pediatric AIDS Clinical Trials Group (PACTG) protocols or were premature infants who had zidovudine concentrations drawn for therapeutic drug monitoring. The data set consisted of 698 serum samples from 83 infants with a mean gestational age at birth of 37.5 weeks (range, 26.0 to 41.5 weeks), mean postnatal age at sampling of 19.3 days (range, 0 to 144 days), and a mean weight at sampling of 3.1 kg (range, 0.71 to 6.0 kg). With use of the program NONMEM and a two-compartment open model, the influences of demographic and clinical factors on the elimination rate constant (k10), volume of distribution of the central compartment (Vc) and bioavailability (F1) were examined. RESULTS: Zidovudine elimination was slow immediately after birth but increased rapidly in term infants during the first weeks of life, reaching a plateau by 4 to 8 weeks of age. In premature infants, zidovudine elimination increased at a much slower rate than in the term infants. Gender, race, and exposure to didanosine or nevirapine had no impact on zidovudine elimination. Bioavailability was increased in infants less than 14 days old. CONCLUSIONS: Zidovudine elimination kinetics undergo large increases during the first months of life, and the pattern of maturation is different in term and preterm infants. Higher bioavailability in younger infants is consistent with decreased first-pass metabolism associated with reduced clearance.

Population pharmacokinetics of dapsone in children with human immunodeficiency virus infection.

BACKGROUND: Previous studies of dapsone pharmacokinetics in children have been too small to allow assessment of the relationships between dapsone pharmacokinetic parameters and patient characteristics or markers of efficacy and toxicity. METHODS: We used population analysis to estimate dapsone pharmacokinetic parameters in children participating in a phase I/II study of daily and weekly dapsone in children with human immunodeficiency virus (HIV) infection. With use of the program NONMEM and a 1-compartment open model, the influence of demographic and clinical characteristics on oral clearance (CL/F) and oral volume of distribution (V/F) were examined. Measures of drug exposure (area under the concentration-time curve [AUC] and predicted concentrations just before and 2 hours after administration) were estimated for each patient and correlated with markers of efficacy and toxicity. RESULTS: Sixty children (median age, 3 years; age range, 2 months to 12 years) contributed 412 dapsone concentrations collected after 175 study doses. Final parameter estimates were 1.40 L/kg for V/F, 0.0283 L/kg/h for CL/F, and 2.66 for the absorption rate constant. Of the clinical characteristics evaluated, dapsone CL/F was significantly increased by 50% in children taking rifabutin, by 39% in black children, and by 38% in children younger than 2 years old. Although no significant correlations were found between any dapsone exposure parameter and markers of toxicity, increased AUC was associated with a decreased risk of Pneumocystis carinii pneumonia (PCP). CONCLUSION: Ethnicity, age, and concomitant rifabutin use were associated with dapsone CL/F, with more rapid clearance observed in black children, children younger than 2 years old, and children receiving rifabutin. Dapsone pharmacokinetic parameters were not associated with toxicity, but higher dapsone AUC was associated with decreased risk of PCP. Monitoring of serum dapsone levels may be needed for optimal management of dapsone for PCP prophylaxis in children.

Circulating catecholamine concentrations in cocaine-exposed neonates: a pilot study.

Twenty newborns, 12 with prenatal exposure to cocaine and an unexposed control group of 8, were studied to determine concentrations of circulating catecholamines and their relationship to newborn behavior. Birth weight of the cocaine-exposed neonates was significantly lower than that of the control group. Gestational age, length, and head circumference of the cocaine-exposed neonates were also lower, although the differences did not reach statistical significance. Between 24 and 48 hours of age, circulating concentrations of norepinephrine, dopamine, and the catecholamine precursor dihydroxyphenylalanine were measured and behavior was assessed using the Neonatal Behavioral Assessment Scale. Mean dihydroxyphenylalanine concentrations were increased in the cocaine-exposed newborns (10.3 ng/mL vs 5.9 ng/mL, P = .055), while there was no difference between the groups in mean norepinephrine or dopamine concentrations. There was a significant negative correlation between norepinephrine concentration and orientation cluster score for the cocaine-exposed newborns (r2 = .6979, P = .005). norepinephrine concentration did not correlate with the score for any other behavioral cluster, nor did dopamine or dihydroxyphenylalanine concentration correlate with the score for any cluster. These preliminary data from a pilot study suggest that catecholamine activity is increased in cocaine-exposed newborns and may play a role in neurobehavioral disturbances associated with prenatal exposure to this drug.

Cerebrospinal fluid monoamine precursors and metabolites in human neonates following in utero cocaine exposure: a preliminary study.

BACKGROUND: Cocaine acts in the central nervous system by increasing dopamine release and inhibiting the reuptake of dopamine and other monoaminergic neurotransmitters. Prenatal cocaine exposure may cause neurochemical changes in developing monoaminergic neurons and might alter brain structure and function. No data have been published on central nervous system monoamine precursors and metabolites in human neonates exposed prenatally to cocaine. METHODS: Cerebrospinal fluid (CSF) was obtained from neonates undergoing lumbar puncture to rule out infection. The CSF was analyzed for the neurotransmitter precursors and metabolites tryptophan, tyrosine, 3-methoxy-4-hydroxyphenylglycol, homovanillic acid, and 5-hydroxyindoleacetic acid. Drug exposure was ascertained by medical record review and urine and meconium assays. RESULTS: Eleven neonates were cocaine-exposed, based on positive meconium or urine assays for benzoylecgonine; 20 were unexposed, based on both negative history and assay. The exposed and unexposed groups did not differ significantly in gender, perinatal stress, clinical illness, or exposure to other illicit drugs, but did differ in mean gestational age, growth parameters, and exposure to cigarettes. Cocaine-exposed neonates had significantly lower levels of CSF homovanillic acid (mean 148.1 vs 218.5 ng/mL, P = .01). The magnitude of this difference was similar after correcting for each of four potential confounding factors, although no longer statistically significant in all cases (P values ranged from .044 to .17). No significant differences were observed for tyrosine, tryptophan, 5-hydroxyindoleacetic acid, or 3-methoxy-4-hydroxyphenylglycol. CONCLUSIONS: These preliminary results suggest an association between prenatal cocaine exposure and decreased CSF homovanillic acid, the principal metabolite of dopamine. Prenatal cocaine exposure may result in changes in central dopaminergic systems in the human neonate.

Late dose-response effects of prenatal cocaine exposure on newborn neurobehavioral performance.

OBJECTIVE: To determine in a representative sample of full-term urban newborns of English-speaking mothers whether an immediate or late dose-response effect could be demonstrated between prenatal cocaine exposure and newborn neurobehavioral performance, controlling for confounding factors. METHODS: The Neonatal Behavioral Assessment Scale (NBAS) was administered by masked examiners to a total sample of 251 clinically healthy, full-term infants at 2 days and/or 17 days. Three in utero cocaine exposure groups were defined: heavily exposed (n = 44, > 75th percentile self-reported days of use during pregnancy and/or > 75th percentile of meconium benzoylecognine concentration); lightly exposed (n = 79, less than both 75th percentiles); and unexposed (n = 101, no positive biological or self-report marker). At the 3-week examination there were 38 heavily exposed, 73 lightly exposed, and 94 unexposed infants. Controlling for infant birth weight, gestational age, infant age at the time of examination, mothers' age, perinatal risk, obstetric medication, and alcohol, marijuana, and cigarette use, a regression analysis evaluated the effects of levels of cocaine exposure on NBAS performance. RESULTS: No neurobehavioral effects of exposure on the newborn NBAS cluster scores or on the qualifier scores were found when confounders were controlled for at 2 to 3 days of age. At 3 weeks, after controlling for covariates, a significant dose effect was observed, with heavily exposed infants showing poorer state regulation and greater excitability. CONCLUSIONS: These findings demonstrate specific dose-related effects of cocaine on 3-week neurobehavioral performance, particularly for the regulation of arousal, which was not observed in the first few days of life.

Level of in utero cocaine exposure and neonatal ultrasound findings.

OBJECTIVE: To assess whether there is an association between the level of in utero cocaine exposure and findings on neonatal cranial ultrasound, controlling for potentially confounding variables. STUDY DESIGN: In a prospective longitudinal study, three cocaine exposure groups were defined by maternal report and infant meconium assay: unexposed, heavier cocaine exposure (>75th percentile self-reported days of use or of meconium benzoylecogonine concentration) or lighter cocaine exposure (all others). Neonatal ultrasounds from 241 well, term infants were read by a single radiologist who was masked to the exposure group. RESULTS: Infants with lighter cocaine exposure did not differ from the unexposed infants on any ultrasound findings. After controlling for infant gender, gestational age, and birth weight z scores and for maternal parity, blood pressure in labor, ethnicity, and use of cigarettes, alcohol, and marijuana during pregnancy, the more heavily cocaine-exposed infants were more likely than the unexposed infants to show subependymal hemorrhage in the caudothalamic groove (covariate adjusted odds ratio: 3.88; 95% confidence interval: 1.45, 10.35). CONCLUSIONS: This is the first study to demonstrate that ultrasound findings suggestive of vascular injury to the neonatal central nervous system are related to the level of prenatal cocaine exposure. Inconsistency in previous research in identifying an association between prenatal cocaine exposure and neonatal cranial ultrasound findings may reflect failure to consider dose effects.

Nevirapine: pharmacokinetic considerations in children and pregnant women.

Nevirapine is a potent non-nucleoside inhibitor of HIV-1 reverse transcriptase. It is effective when used as part of combination therapy to treat HIV-1-infected individuals and as monotherapy for prevention of mother-to-child HIV-1 transmission. Nevirapine pharmacokinetics are characterised by rapid absorption and distribution, followed by prolonged elimination. Nevirapine is generally well tolerated. The most common toxicity is rash, which is usually mild and self-limiting. The primary route of nevirapine elimination is through metabolism by the cytochrome P450 enzyme system. Nevirapine elimination accelerates during long term administration because of autoinduction of the enzymes involved in its elimination pathway. The recommended regimen for adults is nevirapine 200mg once daily for 2 weeks, followed by 200mg twice daily. Nevirapine elimination is prolonged in pregnant women during labour and in newborns. A regimen of a single 200mg oral dose administered to the mother during labour and a single 2 mg/kg dose administered to the newborn at 48 to 72 hours after birth maintains serum nevirapine concentrations above 100 microg/L (10 times the in vitro 50% inhibitory concentration against wild-type HIV-1) throughout the first week of life. This limited regimen has been shown to be extremely well tolerated and to reduce mother-to-child transmission by nearly 50% in mothers and infants receiving no other antiretrovirals. There are few data describing the safety and pharmacokinetics of nevirapine during long term use in pregnancy. In children, nevirapine elimination accelerates during the first years of life, reaching a maximum at around 2 years of age, followed by a gradual decline during the rest of childhood. Children should receive 4 mg/kg once daily for the first 2 weeks of therapy, followed by 7 mg/kg doses twice daily if below the age of 8 years or 4 mg/kg twice daily if older than 8 years. Alternatively, children may receive 150 mg/m2 across all ages, once daily for the first 2 weeks of therapy followed by the same dose twice daily.

Nevirapine pharmacokinetics in pregnant women and in their infants after in utero exposure.

The safety, toxicity and pharmacokinetics of nevirapine were studied in HIV-infected pregnant women beginning chronic therapy late in the third trimester and in their infants. Initial dose pharmacokinetic profiles in the pregnant women were similar to those seen in nonpregnant adults. Serum nevirapine concentrations fell below the 100-ng/ml target concentration by Day 7 of life in four infants, suggesting that nevirapine elimination is accelerated in these infants compared with newborns whose mothers receive only a single intrapartum nevirapine dose.

Toxicity and efficacy of daily vs. weekly dapsone for prevention of Pneumocystis carinii pneumonia in children infected with human immunodeficiency virus. ACTG 179 Study Team. AIDS Clinical Trials Group.

BACKGROUND: Dapsone is an alternative drug for Pneumocystis carinii pneumonia (PCP) prophylaxis in individuals intolerant to trimethoprim-sulfamethoxazole (T/S). There are, however, few data on the pharmacokinetics, toxicity or efficacy of dapsone in children. Design. Randomized, multicenter trial comparing daily (1 or 2 mg/kg) with weekly (4 mg/kg) dapsone regimens in 94 HIV-infected children intolerant to T/S. METHODS: Hematologic and hepatic toxicity was monitored, as well as the occurrence of skin rash, PCP or death. RESULTS: Initial pharmacokinetic data indicated that adequate serum dapsone concentrations were not achieved with the daily 1-mg/kg regimen; the daily dose was then increased to 2 mg/kg. Both short and long term hematologic toxicities were marginally greater in children receiving the daily 2 mg/kg compared with the weekly regimen. Allergic skin rashes were similar in children receiving the daily and weekly regimens (17% in both) and were not associated with prior history of rash with T/S. PCP occurred most frequently with the daily 1-mg/kg regimen (22.0 cases/100 patient years), least frequently with the daily 2-mg/kg regimen (0 case/100 patient years) and at intermediate frequency with the weekly regimen (9.5 cases/100 patient years). More deaths were observed in patients receiving the daily than the weekly regimen (8 vs. 2, respectively), although the deaths were not directly attributable to dapsone treatment. CONCLUSION: Although a weekly dapsone regimen of 4 mg/kg produced less hematologic toxicity than a daily regimen of 2 mg/kg, this advantage was offset by a trend toward higher breakthrough rates of PCP.

Antiretroviral pharmacology in pregnant women and their newborns.

The physiologic changes of pregnancy have an impact on antiretroviral pharmacokinetic parameters, but the effect is generally not of sufficient magnitude to warrant alterations in dosing. Although administration of oral zidovudine during labor may not provide equivalent serum drug exposure as with continuous intravenous infusion, the clinical relevance of the difference is unknown. Nevirapine is well absorbed during labor, and sufficient drug for prophylaxis against perinatal transmission crosses the placenta if an oral dose is administered to the mother at least 1 hour before delivery. Placental transfer of reverse transcriptase inhibitors is good, whereas preliminary data suggest that protease inhibitors do not cross the placenta well. The use of antiretrovirals during pregnancy is becoming increasingly common, although their safety, toxicity, and teratogencity in pregnancy have not been well described. Normal growth and development have a profound impact on the pharmacokinetics of antiretrovirals in newborns and infants. Washout elimination of transplacentally acquired drug is slow. The pattern of increase in drug clearance over time will depend on the specific elimination pathway for the agent. Dosing regimens must take into account developmental changes in clearance and appropriate scaling for size. Adherence to antiretroviral regimens is a critical factor in determining the success of prophylactic and therapeutic regimens and is made difficult by the inability of infants to swallow pills and capsules.

Fetal liver ultrasound measurements in isoimmunized pregnancies.

Sixteen isoimmunized pregnancies at risk for erythroblastosis fetalis were managed by serial amniocenteses for bilirubin delta optical density at 450 nm (delta OD450). Before amniocentesis each fetus was evaluated ultrasonically and the fetal liver size, the abdominal circumference, and the umbilical vein diameter, in both the fetal liver and the umbilical cord, were measured. The ultrasonically determined fetal liver size, as well as its growth rate, was found to be greater than normal during the last two weeks before intervention (intrauterine transfusion or delivery) in all eight fetuses with severe hemolytic disease. The umbilical vein diameter in the fetal liver was above normal in only one fetus, whereas the abdominal circumference was increased in only three of the eight severely affected fetuses. These data suggest that serial fetal liver ultrasound measurements may be useful as an adjunct to amniotic fluid analysis to predict the severely affected fetus in need of prompt intervention (intrauterine transfusion or delivery).