Optimal Antimalarial Dose Regimens for Sulfadoxine-Pyrimethamine with or without Azithromycin in Pregnancy Based on Population Pharmacokinetic Modeling.

Optimal dosing of sulfadoxine-pyrimethamine (SP) as intermittent preventive treatment in pregnancy remains to be established, particularly when coadministered with azithromycin (AZI). To further characterize SP pharmacokinetics in pregnancy, plasma concentration-time data from 45 nonpregnant and 45 pregnant women treated with SP-AZI (n = 15 in each group) and SP-chloroquine (n = 30 in each group) were analyzed. Population nonlinear mixed-effect pharmacokinetic models were developed for pyrimethamine (PYR), sulfadoxine (SDOX), and N-acetylsulfadoxine (the SDOX metabolite NASDOX), and potential covariates were included. Pregnancy increased the relative clearance (CL/F) of PYR, SDOX, and NASDOX by 48, 29, and 70%, respectively, as well as the relative volumes of distribution (V/F) of PYR (46 and 99%) and NASDOX (46%). Coadministration of AZI resulted in a greater increase in PYR CL/F (80%) and also increased NASDOX V/F by 76%. Apparent differences between these results and those of published studies of SP disposition may reflect key differences in study design, including the use of an early postpartum follow-up study rather than a nonpregnant comparator group. Simulations based on the final population model demonstrated that, compared to conventional single-dose SP in nonpregnant women, two such doses given 24 h apart should ensure that pregnant women have similar drug exposure, while three daily SP doses may be required if SP is given with AZI. The results of past and ongoing trials using recommended adult SP doses with or without AZI in pregnant women may need to be interpreted in light of these findings and consideration given to using increased doses in future trials.

Population PK modelling and simulation based on fluoxetine and norfluoxetine concentrations in milk: a milk concentration-based prediction model.

AIMS: Population pharmacokinetic (pop PK) modelling can be used for PK assessment of drugs in breast milk. However, complex mechanistic modelling of a parent and an active metabolite using both blood and milk samples is challenging. We aimed to develop a simple predictive pop PK model for milk concentration-time profiles of a parent and a metabolite, using data on fluoxetine (FX) and its active metabolite, norfluoxetine (NFX), in milk. METHODS: Using a previously published data set of drug concentrations in milk from 25 women treated with FX, a pop PK model predictive of milk concentration-time profiles of FX and NFX was developed. Simulation was performed with the model to generate FX and NFX concentration-time profiles in milk of 1000 mothers. This milk concentration-based pop PK model was compared with the previously validated plasma/milk concentration-based pop PK model of FX. RESULTS: Milk FX and NFX concentration-time profiles were described reasonably well by a one compartment model with a FX-to-NFX conversion coefficient. Median values of the simulated relative infant dose on a weight basis (sRID: weight-adjusted daily doses of FX and NFX through breastmilk to the infant, expressed as a fraction of therapeutic FX daily dose per body weight) were 0.028 for FX and 0.029 for NFX. The FX sRID estimates were consistent with those of the plasma/milk-based pop PK model. CONCLUSIONS: A predictive pop PK model based on only milk concentrations can be developed for simultaneous estimation of milk concentration-time profiles of a parent (FX) and an active metabolite (NFX).

Artemisinin-naphthoquine combination therapy for uncomplicated pediatric malaria: a pharmacokinetic study.

Artemisinin-naphthoquine (ART-NQ) is a coformulated antimalarial therapy marketed as a single-dose treatment in Papua New Guinea and other tropical countries. To build on limited knowledge of the pharmacokinetic properties of the components, especially the tetra-aminoquinoline NQ, we studied ART-NQ disposition in Papua New Guinea children aged 5 to 12 years with uncomplicated malaria, comparing a single dose (15 and 6 mg/kg of body weight) administered with water (group 1; n = 13), a single dose (22 and 9 mg/kg) with milk (group 2) (n = 17), and two daily doses of 22 and 9 mg/kg with water (group 3; n = 16). The plasma NQ concentration was assayed by high-performance liquid chromatography, and the plasma ART concentration was assayed using liquid chromatography-mass spectrometry. Population-based multicompartment pharmacokinetic models for NQ and ART were developed. NQ disposition was best characterized by a three-compartment model with a mean absorption half-life (t(1/2)) of 1.0 h and predicted median maximum plasma concentrations that ranged as high as 57 µg/liter after the second dose in group 3. The mean NQ elimination t(1/2) was 22.8 days; clearance relative to bioavailability (CL/F) was 1.1 liters/h/kg; and volume at steady state relative to bioavailability (V(ss)/F) was 710 liters/kg. Administration of NQ with fat (8.5 g; 615 kJ) versus water was associated with 25% increased bioavailability. ART disposition was best characterized by a two-compartment model with a mean CL/F (4.1 liters/h/kg) and V/F (21 liters/kg) similar to those of previous studies. There was a 77% reduction in the bioavailability of the second ART dose (group 3). NQ has pharmacokinetic properties that confirm its potential as an artemisinin partner drug for treatment of uncomplicated pediatric malaria.

Pharmacokinetic comparison of two piperaquine-containing artemisinin combination therapies in Papua New Guinean children with uncomplicated malaria.

Pharmacokinetic differences between piperaquine (PQ) base and PQ tetraphosphate were investigated in 34 Papua New Guinean children aged 5 to 10 years treated for uncomplicated malaria with artemisinin-PQ (ART-PQ) base or dihydroartemisinin-PQ (DHA-PQ) tetraphosphate. Twelve children received ART-PQ base (two daily doses of 3 mg of ART and 18 mg of PQ base as granules/kg of body weight) as recommended by the manufacturer, with regular clinical assessment and blood sampling over 56 days. PQ concentrations in plasma samples collected from 22 children of similar ages with malaria in a previously published pharmacokinetic study of DHA-PQ tetraphosphate (three daily doses of 2.5 mg of ART and 20 mg of PQ tetraphosphate as tablets/kg of body weight) were available for comparison. The disposition of ART was also assessed in the 12 children who received ART-PQ base. Plasma PQ was assayed by high-performance liquid chromatography with UV detection, and ART was assayed using liquid chromatography-mass spectrometry. Multicompartment pharmacokinetic models for PQ and ART were developed using a population-based approach. ART-PQ base was well tolerated, and initial fever abatement and parasite clearance were prompt. There were no differences between the two treatments in the values for the PQ area under the concentration-time curve from time zero to infinity (AUC(0-∞)), with medians of 49,451 (n = 12) and 44,556 (n = 22) µg · h/liter for ART-PQ base and DHA-PQ tetraphosphate, respectively. Recurrent parasitemia was associated with lower PQ exposure. Using a two-compartment ART model, the median AUC(0-∞) was 1,652 µg · h/liter. There was evidence of autoinduction of ART metabolism (relative bioavailability for the second dose, 0.27). These and previously published data suggest that a 3-day ART-PQ base regimen should be further evaluated, in line with World Health Organization recommendations for all artemisinin combination therapies.

Development of a population pharmacokinetic model for parecoxib and its active metabolite valdecoxib after parenteral parecoxib administration in children.

BACKGROUND: Parecoxib is a cyclooxygenase-2 selective inhibitor used in management of postoperative pain in adults. This study aimed to provide pediatric pharmacokinetic information for parecoxib and its active metabolite valdecoxib. METHODS: Thirty-eight children undergoing surgery received parecoxib (1 mg/kg IV to a maximum of 40 mg) at induction of anesthesia, and plasma samples were collected for drug measurement. Population pharmacokinetic parameters were estimated using nonlinear mixed effects modeling. Area under the valdecoxib concentration-time curve and time above cyclooxygenase-2 in vitro 50% inhibitory concentration for free valdecoxib were simulated. RESULTS: A three-compartment model best represented parecoxib disposition, whereas one compartment was adequate for valdecoxib. Age was linearly correlated with parecoxib clearance (5.0% increase/yr). There was a sigmoid relationship between age and both valdecoxib clearance and distribution volume. Time to 50% maturation was 87 weeks postmenstrual age for both. In simulations using allometric-based doses the 90% prediction interval of valdecoxib concentration-time curve in children 2-12.7 yr included the mean for adults given 40 mg parecoxib IV. Simulated free valdecoxib plasma concentration remained above the in vitro 50% inhibitory concentrations for more than 12 h. In children younger than 2 yr, a dose reduction is likely required due to ongoing metabolic maturation. CONCLUSIONS: The final pharmacokinetic model gave a robust representation of parecoxib and valdecoxib disposition. Area under the valdecoxib concentration-time curve was similar to that in adults (40 mg), and simulated free valdecoxib concentration was above the cyclooxygenase-2 in vitro 50% inhibitory concentration for free valdecoxib for at least 12 h.

Transfer of parecoxib and its primary active metabolite valdecoxib via transitional breastmilk following intravenous parecoxib use after cesarean delivery: a comparison of naive pooled data analysis and nonlinear mixed-effects modeling.

BACKGROUND: Multimodal analgesia, including nonopioid analgesics, is usually used for several days after cesarean delivery. Because the breastfed infant receives transitional milk during this same period, it is important to know how much of a maternal analgesic drug is received by the infant. We designed this study to estimate infant exposure to parecoxib and its active metabolite valdecoxib (a cyclooxygenase-2 inhibitor) after a single IV maternal dose of parecoxib after cesarean delivery. METHODS: Forty women and their infants participated in the study. Parecoxib (40 mg) was administered IV at a mean of 41 hours after birth. Milk (4 samples) and plasma (1 sample) were collected from the women over the subsequent 24 hours and drug content was measured by liquid chromatography-tandem mass spectrometry. The infants were assessed the day after parecoxib dosing. Absolute (AID) and relative infant doses (RID) of both parecoxib and valdecoxib through milk were estimated by standard methods using the naïve pooled datasets, and where possible milk/plasma (M/P) concentration ratios were calculated. Nonlinear mixed-effects modeling was also used to fit the valdecoxib milk and plasma datasets to a compartmental model and to predict M/P, AID, and RID. RESULTS: M/P ratios (median [interquartile range; IQR]) were 0.5 (0.15 to 1.15) for parecoxib and 0.14 (0.11 to 0.18) for valdecoxib. Using the naïve pooled datasets, AID (drug concentration in milk×daily milk intake/kg) was 0.24 (0.05 to 1.85) µg/kg/day for parecoxib, and 1.82 (1.12 to 2.73) µg/kg/day, for valdecoxib. RID was 0.04 (0.01 to 0.43) % of the weight-adjusted maternal dose (one dose in 24 hours) for parecoxib and 0.47 (0.29 to 0.69) % for valdecoxib (as parecoxib equivalents). Compartmental modeling of valdecoxib alone produced a mean (interindividual variability) M/P of 0.149 (26%), median (IQR) AID of 1.47 (0.96 to 2.03) µg/kg/day, and median (IQR) RID of 0.39 (0.28 to 0.47) %. Neonatal neurologic and adaptive capacity scores (mean=34, 95% CI 33 to 35) were consistent with a normal expected score of 35. CONCLUSIONS: Both the naïve pooling of data and the modeling analyses gave similar results. The RID of both parecoxib and valdecoxib was low. We conclude that a single 40 mg IV dose of the cyclooxygenase-2 inhibitor parecoxib administered to lactating women after cesarean delivery is unlikely to cause adverse effects in breastfed infants.

Buprenorphine exposure in infants of opioid-dependent mothers at birth.

BACKGROUND: Buprenorphine, a partial opioid agonist used in treating opioid dependence, is not approved in Australia for use in pregnancy. Nevertheless, many pregnant women choose to remain on the drug. AIM: To investigate cord/maternal transfer ratios for buprenorphine and norbuprenorphine in women at delivery. METHODS: Maternal and cord serum samples were collected from 10 maternal-infant pairs at delivery. Drug concentrations were measured by liquid chromatography-tandem mass spectrometry. Maternal and infant demographic information was collected. Linear regression was used to assess the relationship between maternal and cord measurements. RESULTS: Median (interquartile range) maternal age was 27 (23.8-32) years, with 90% of the women on buprenorphine before pregnancy. Median infant birthweight was 3148 (3088-3545) g and 60% of infants had neonatal abstinence requiring admission to a neonatal intensive care unit for a median of 8.5 (2.5-16.3) days. Median maternal buprenorphine daily dose was 8.5 mg (range 1-28 mg). Mean (95% confidence interval) cord serum concentrations of buprenorphine and norbuprenorphine were 0.4 (0.3-0.5) µg/L and 1.2 (0.9-1.4) µg/L, respectively. Mean maternal concentrations of buprenorphine and norbuprenorphine were 1.0 (0.6-1.4) µg/L and 1.2 (0.9-1.4) µg/L, respectively. Mean cord/maternal ratios were 0.43 (0.36-0.5) for buprenorphine and 0.53 (0.43-0.63) for norbuprenorphine. Maternal buprenorphine and norbuprenorphine concentrations and ratio of buprenorphine/norbuprenorphine explained 85.7, 69.6 and 94.4%, respectively, of variation in the corresponding cord concentrations. CONCLUSION: Usual therapeutic doses of buprenorphine administered to pregnant women resulted in low concentrations of buprenorphine and norbuprenorphine in maternal serum and a low transfer to the fetal circulation (cord plasma) at birth.

Pharmacokinetics, pharmacodynamics, and allometric scaling of chloroquine in a murine malaria model.

Chloroquine (CQ) is an important antimalarial drug for the treatment of special patient groups and as a comparator for preclinical testing of new drugs. Pharmacokinetic data for CQ in animal models are limited; thus, we conducted a three-part investigation, comprising (i) pharmacodynamic studies of CQ and CQ plus dihydroartemisinin (DHA) in Plasmodium berghei-infected mice, (ii) pharmacokinetic studies of CQ in healthy and malaria-infected mice, and (iii) interspecies allometric scaling for CQ from 6 animal and 12 human studies. The single-dose pharmacodynamic study (10 to 50 mg CQ/kg of body weight) showed dose-related reduction in parasitemia (5- to >500-fold) and a nadir 2 days after the dose. Multiple-dose regimens (total dose, 50 mg/kg CQ) demonstrated a lower nadir and longer survival time than did the same single dose. The CQ-DHA combination provided an additive effect compared to each drug alone. The elimination half-life (t(1/2)), clearance (CL), and volume of distribution (V) of CQ were 46.6 h, 9.9 liters/h/kg, and 667 liters/kg, respectively, in healthy mice and 99.3 h, 7.9 liters/h/kg, and 1,122 liters/kg, respectively, in malaria-infected mice. The allometric equations for CQ in healthy mammals (CL = 3.86 × W(0.56), V = 230 × W(0.94), and t(1/2) = 123 × W(0.2)) were similar to those for malaria-infected groups. CQ showed a delayed dose-response relationship in the murine malaria model and additive efficacy when combined with DHA. The biphasic pharmacokinetic profiles of CQ are similar across mammalian species, and scaling of specific parameters is plausible for preclinical investigations.

Population pharmacokinetics of artemether, lumefantrine, and their respective metabolites in Papua New Guinean children with uncomplicated malaria.

There are sparse published data relating to the pharmacokinetic properties of artemether, lumefantrine, and their active metabolites in children, especially desbutyl-lumefantrine. We studied 13 Papua New Guinean children aged 5 to 10 years with uncomplicated malaria who received the six recommended doses of artemether (1.7 mg/kg of body weight) plus lumefantrine (10 mg/kg), given with fat over 3 days. Intensive blood sampling was carried out over 42 days. Plasma artemether, dihydroartemisinin, lumefantrine, and desbutyl-lumefantrine were assayed using liquid chromatography-mass spectrometry or high-performance liquid chromatography. Multicompartmental pharmacokinetic models for a drug plus its metabolite were developed using a population approach that included plasma artemether and dihydroartemisinin concentrations below the limit of quantitation. Although artemether bioavailability was variable and its clearance increased by 67.8% with each dose, the median areas under the plasma concentration-time curve from 0 h to infinity (AUC(0-∞)s) for artemether and dihydroartemisinin (3,063 and 2,839 µg · h/liter, respectively) were similar to those reported previously in adults with malaria. For lumefantrine, the median AUC(0-∞) (459,980 µg · h/liter) was also similar to that in adults with malaria. These data support the higher dose recommended for children weighing 15 to 35 kg (35% higher than that for a 50-kg adult) but question the recommendation for a lower dose in children weighing 12.5 to 15 kg. The median desbutyl-lumefantrine/lumefantrine ratio in the children in our study was 1.13%, within the range reported for adults and higher at later time points because of the longer desbutyl-lumefantrine terminal elimination half-life. A combined desbutyl-lumefantrine and lumefantrine AUC(0-∞) weighted on in vitro antimalarial activity was inversely associated with recurrent parasitemia, suggesting that both the parent drug and the metabolite contribute to the treatment outcome of artemether-lumefantrine.

Desbutyl-lumefantrine is a metabolite of lumefantrine with potent in vitro antimalarial activity that may influence artemether-lumefantrine treatment outcome.

Desbutyl-lumefantrine (DBL) is a metabolite of lumefantrine. Preliminary data from Plasmodium falciparum field isolates show greater antimalarial potency than, and synergy with, the parent compound and synergy with artemisinin. In the present study, the in vitro activity and interactions of DBL were assessed from tritium-labeled hypoxanthine uptake in cultures of the laboratory-adapted strains 3D7 (chloroquine sensitive) and W2mef (chloroquine resistant). The geometric mean 50% inhibitory concentrations (IC(50)s) for DBL against 3D7 and W2mef were 9.0 nM (95% confidence interval, 5.7 to 14.4 nM) and 9.5 nM (95% confidence interval, 7.5 to 11.9 nM), respectively, and those for lumefantrine were 65.2 nM (95% confidence interval, 42.3 to 100.8 nM) and 55.5 nM (95% confidence interval, 40.6 to 75.7 nM), respectively. An isobolographic analysis of DBL and lumefantrine combinations showed no interaction in either laboratory-adapted strain but mild synergy between DBL and dihydroartemisinin (sums of the fractional inhibitory concentrations of 0.92 [95% confidence interval, 0.87 to 0.98] and 0.94 [95% confidence interval, 0.90 to 0.99] for 3D7 and W2mef, respectively). Using a validated ultra-high-performance liquid chromatography-tandem mass spectrometry assay and 94 day 7 samples from a previously reported intervention trial, the mean plasma DBL was 31.9 nM (range, 1.3 to 123.1 nM). Mean plasma DBL concentrations were lower in children who failed artemether-lumefantrine treatment than in those with an adequate clinical and parasitological response (ACPR) (P = 0.053 versus P > 0.22 for plasma lumefantrine and the plasma lumefantrine-to-DBL ratio, respectively). DBL is more potent than the parent compound and mildly synergistic with dihydroartemisinin. These properties and the relationship between day 7 plasma concentrations and the ACPR suggest that it could be a useful alternative to lumefantrine as a part of artemisinin combination therapy.

Pharmacokinetic properties of conventional and double-dose sulfadoxine-pyrimethamine given as intermittent preventive treatment in infancy.

Intermittent preventive treatment in infancy (IPTi) entails routine administration of antimalarial treatment doses at specified times in at-risk infants. Sulfadoxine-pyrimethamine (SDX/PYR) is a combination that has been used as first-line IPTi. Because of limited pharmacokinetic data and suggestions that higher milligram/kilogram pediatric doses than recommended should be considered, we assessed SDX/PYR disposition, randomized to conventional (25/1.25 mg/kg of body weight) or double (50/2.5 mg/kg) dose, in 70 Papua New Guinean children aged 2 to 13 months. Blood samples were drawn at baseline, 28 days, and three time points randomly selected for each infant at 4 to 8 h or 2, 5, 7, 14, or 21 days. Plasma SDX, PYR, and N(4)-acetylsulfadoxine (NSX, the principal metabolite of SDX) were assayed by high-performance liquid chromatography (HPLC). Using population modeling incorporating hepatic maturation and cystatin C-based renal function, two-compartment models provided best fits for PYR and SDX/NSX plasma concentration profiles. The area under the plasma concentration-time curve from 0 h to infinity (AUC(0-∞)) was greater with the double dose versus the conventional dose of PYR (4,915 versus 2,844 µg/day/liter) and SDX (2,434 versus 1,460 mg/day/liter). There was a 32% reduction in SDX relative bioavailability with the double dose but no evidence of dose-dependent metabolism. Terminal elimination half-lives (15.6 days for PYR, 9.1 days for SDX) were longer than previously reported. Both doses were well tolerated without changes in hemoglobin or hepatorenal function. Five children in the conventional and three in the double-dose group developed malaria during follow-up. These data support the potential use of double-dose SDX/PYR in infancy, but further studies should examine the influence of hepatorenal maturation in very young infants.

A trial of combination antimalarial therapies in children from Papua New Guinea.

BACKGROUND: Malaria control is difficult where there is intense year-round transmission of multiple plasmodium species, such as in Papua New Guinea. METHODS: Between April 2005 and July 2007, we conducted an open-label, randomized, parallel-group study of conventional chloroquine-sulfadoxine-pyrimethamine and artesunate-sulfadoxine-pyrimethamine, dihydroartemisinin-piperaquine, and artemether-lumefantrine in children in Papua New Guinea 0.5 to 5 years of age who had falciparum or vivax malaria. The primary end point was the rate of adequate clinical and parasitologic response at day 42 after the start of treatment with regard to Plasmodium falciparum, after correction for reinfections identified through polymerase-chain-reaction (PCR) genotyping of polymorphic loci in parasite DNA. Secondary end points included the rate of adequate clinical and parasitologic response at day 42 with regard to P. vivax without correction through PCR genotyping. RESULTS: Of 2802 febrile children screened, 482 with falciparum malaria and 195 with vivax malaria were included. The highest rate of adequate clinical and parasitologic response for P. falciparum was in the artemether-lumefantrine group (95.2%), as compared with 81.5% in the chloroquine-sulfadoxine-pyrimethamine group (P=0.003), 85.4% in the artesunate-sulfadoxine-pyrimethamine group (P=0.02), and 88.0% in the dihydroartemisinin-piperaquine group (P=0.06). The rate of adequate clinical and parasitologic response for P. vivax in the dihydroartemisinin-piperaquine group (69.4%) was more than twice that in each of the other three treatment groups. The in vitro chloroquine and piperaquine levels that inhibited growth of local P. falciparum isolates by 50% correlated significantly (P<0.001). Rash occurred more often with artesunate-sulfadoxine-pyrimethamine and dihydroartemisinin-piperaquine than with chloroquine-sulfadoxine-pyrimethamine (P=0.004 for both comparisons). CONCLUSIONS: The most effective regimens were artemether-lumefantrine against P. falciparum and dihydroartemisinin-piperaquine against P. vivax. The relatively high rate of treatment failure with dihydroartemisinin-piperaquine against P. falciparum may reflect cross-resistance between chloroquine and piperaquine. (Australian New Zealand Clinical Trials Registry number, ACTRN12605000550606.)

Population pharmacokinetic modeling of tramadol and its O-desmethyl metabolite in plasma and breast milk.

PURPOSE: The aim of this investigation was to demonstrate that nonlinear mixed-effects population pharmacokinetic (PK) modeling can be used to evaluate data from studies of drug transport/excretion into human milk and hence to estimate infant exposure. METHODS: A sparse dataset from a previously published study of the use of oral tramadol for post-cesarean pain management in 75 lactating women was used. Milk and plasma samples were collected during days 2-4 of lactation, and tramadol and O-desmethyltramadol (ODT) concentration measurements in these samples were available. Absolute infant dose was obtained from the concentration measurements and estimated milk volume ingested, and expressed in micrograms per kilogram per day. Relative infant dose was calculated as a percentage of the absolute infant dose divided by the maternal dose (µg/kg/day). Nonlinear mixed-effects modeling was used to fit a population PK model to the data. RESULTS: The disposition of tramadol and ODT in plasma and the transition of these substances into milk were characterized by a five-compartment population PK mixture model with first-order absorption. The polymorphic ODT formation clearance in the plasma compartment was able to be characterized in both CYP2D6-poor and -extensive metabolizers. Milk creamatocrit was a significant covariate in ODT transfer between the plasma and milk compartments. The estimated relative infant doses in extensive and poor metabolizers, respectively, were 2.16 ± 0.57 and 2.60 ± 0.57% for tramadol, and 0.93 ± .20 and 0.47 ± 0.10% for ODT. CONCLUSIONS: This study demonstrates that a population PK approach with sparse sampling of analytes in milk and plasma can yield quality information about the transfer process and that it also can be used to estimate the extent of infant exposure to maternal drugs via milk.

Duloxetine transfer across the placenta during pregnancy and into milk during lactation.

OBJECTIVE: Duloxetine is an efficacious antidepressant; however, its safety during the perinatal period is uncertain. The objective of this study was to assess the transfer across the placenta and provide data on infant exposure to duloxetine via breast milk. METHODS: A multiparous 31-year-old woman with recurrent melancholic depression had responded poorly to previous antidepressants, but had a full remission on duloxetine. She elected to remain on duloxetine for her third pregnancy and while breastfeeding. She gave birth to a healthy term infant and there were no adverse events noted for the infant exposed to duloxetine. Duloxetine concentration was measured chromatographically in maternal and infant serum collected at birth, and in maternal milk and plasma and infant plasma 18 days later, (C/M) concentration ratio was calculated. Absolute and relative infant doses via milk were estimated and the percent drug in infant versus mother's plasma was calculated. RESULTS: Cord/maternal serum concentration ratio for duloxetine was 0.12. Absolute infant dose via milk was 7.6 µg/L and relative infant dose was 0.81%. The ratio of drug in the infant's plasma to that in maternal plasma during lactation also gave a 0.82% infant exposure estimate. CONCLUSIONS: The low C/M ratio suggests a limited transfer across the placenta. The relative infant dose via milk was low by comparison to most other antidepressants, and this estimate confirmed the amount of drug in infant plasma during lactation. Our data suggest that duloxetine may be used in pregnancy and lactation for selected patients in whom other antidepressants have not been successful.

Estimation of desvenlafaxine transfer into milk and infant exposure during its use in lactating women with postnatal depression.

This study characterises the extent of desvenlafaxine transfer into milk and provides data on infant exposure to desvenlafaxine via breast milk in ten women with postnatal depression and their breastfed infants. Desvenlafaxine concentration in milk and plasma was measured chromatographically in milk and in maternal and infant plasma collected at steady state. Theoretic and relative infant doses via milk were estimated and the per cent drug in infant versus mother's plasma was calculated. Theoretic infant dose via milk was 85 (53-117) µg kg(-1) day(-1) (mean and 95% confidence interval) and relative infant dose was 6.8% (5.5-8.1%). The ratio of drug in infant/maternal plasma also gave an infant exposure estimate of 4.8% (3.5-6.2%) for all ten infants and 5.3% (4.2-5.7%) in the eight infants who were exclusively breastfed. No adverse effects were seen in the infants. The relative infant dose was similar to that for previous studies using venlafaxine and was supported by a separate exposure measure using the ratio of drug in the infant's plasma relative to that in the mother's plasma. The theoretic infant dose of desvenlafaxine was 41-45% of that for venlafaxine and its metabolite desvenlafaxine in previous studies, reflecting the lower recommended maternal dose for desvenlafaxine. Although our data for desvenlafaxine use in lactation are encouraging and there are supporting data from venlafaxine studies, more patients and their infants need to be studied before the safety of desvenlafaxine as a single therapeutic agent can be fully assessed.

Pharmacokinetics of chloroquine and monodesethylchloroquine in pregnancy.

In order to determine the pharmacokinetic disposition of chloroquine (CQ) and its active metabolite, desethylchloroquine (DECQ), when administered as intermittent presumptive treatment in pregnancy (IPTp) for malaria, 30 Papua New Guinean women in the second or third trimester of pregnancy and 30 age-matched nonpregnant women were administered three daily doses of 450 mg CQ (8.5 mg/kg of body weight/day) in addition to a single dose of sulfadoxine-pyrimethamine. For all women, blood was taken at baseline; at 1, 2, 4, 6, 12, 18, 24, 30, 48, and 72 h posttreatment; and at 7, 10, 14, 28, and 42 days posttreatment. Plasma was subsequently assayed for CQ and DECQ by high-performance liquid chromatography, and population pharmacokinetic modeling was performed. Pregnant subjects had significantly lower area under the plasma concentration-time curve for both CQ (35,750 versus 47,892 microg.h/liter, P < 0.001) and DECQ (23,073 versus 41,584 microg.h/liter, P < 0.001), reflecting significant differences in elimination half-lives and in volumes of distribution and clearances relative to bioavailability. Reduced plasma concentrations of both CQ and DECQ could compromise both curative efficacy and posttreatment prophylactic properties in pregnant patients. Higher IPTp CQ doses may be desirable but could increase the risk of adverse hemodynamic effects.

Pharmacokinetic properties of azithromycin in pregnancy.

Azithromycin (AZI) is an azalide antibiotic with antimalarial activity that is considered safe in pregnancy. To assess its pharmacokinetic properties when administered as intermittent preventive treatment in pregnancy (IPTp), two 2-g doses were given 24 h apart to 31 pregnant and 29 age-matched nonpregnant Papua New Guinean women. All subjects also received single-dose sulfadoxine-pyrimethamine (SP) (1,500 mg or 75 mg) or chloroquine (450-mg base daily for 3 days). Blood samples were taken at 0, 1, 2, 3, 6, 12, 24, 32, 40, 48, and 72 h and on days 4, 5, 7, 10, and 14 for AZI assay by ultra-high-performance liquid chromatography-tandem mass spectrometry. The treatments were well tolerated. Using population pharmacokinetic modeling, a three-compartment model with zero-order followed by first-order absorption and no lag time provided the best fit. The areas under the plasma concentration-time curve (AUC(0-infinity)) (28.7 and 31.8 mg.h liter(-1) for pregnant and nonpregnant subjects, respectively) were consistent with the results of previous studies, but the estimated terminal elimination half-lives (78 and 77 h, respectively) were generally longer. The only significant relationship for a range of potential covariates, including malarial parasitemia, was with pregnancy, which accounted for an 86% increase in the volume of distribution of the central compartment relative to bioavailability without a significant change in the AUC(0-infinity). These data suggest that AZI can be combined with compounds with longer half-lives, such as SP, in combination IPTp without the need for dose adjustment.

In vitro sensitivity of Plasmodium falciparum to conventional and novel antimalarial drugs in Papua New Guinea.

OBJECTIVE: Recent clinical studies have shown high rates of malaria treatment failure in endemic areas of Papua New Guinea (PNG), necessitating a change of treatment from chloroquine (CQ) or amodiaquine (AQ) plus sulphadoxine-pyrimethamine to the artemisinin combination therapy (ACT) artemether plus lumefantrine (LM). To facilitate the monitoring of antimalarial drug resistance in this setting, we assessed the in vitro sensitivity of Plasmodium falciparum isolates from Madang Province. METHODS: A validated colorimetric lactate dehydrogenase assay was used to assess growth inhibition of 64 P. falciparum isolates in the presence of nine conventional or novel antimalarial drugs [CQ, AQ, monodesethyl-amodiaquine (DAQ), piperaquine (PQ), naphthoquine (NQ), mefloquine (MQ), LM, dihydroartemisinin and azithromycin (AZ)]. RESULTS: The geometric mean (95% confidence interval) concentration required to inhibit parasite growth by 50% (IC(50)) was 167 (141-197) nM for CQ, and 82% of strains were resistant (threshold 100 nM), consistent with near-fixation of the CQ resistance-associated pfcrt allele in PNG. Except for AZ [8.351 (5.418-12.871) nM], the geometric mean IC(50) for the other drugs was <20 nM. There were strong associations between the IC(50)s of 4-aminoquinoline (CQ, AQ, DAQ and NQ), bisquinoline (PQ) and aryl aminoalcohol (MQ) compounds suggesting cross-resistance, but LM IC(50) only correlated with that of MQ. Conclusions Most PNG isolates are resistant to CQ in vitro but not to other ACT partner drugs. The non-isotopic semi-automated high-throughput nature of the Plasmodium lactate dehydrogenase assay facilitates the convenient serial assessment of local parasite sensitivity, so that emerging resistance can be identified with relative confidence at an early stage.

Therapeutic drug monitoring for busulfan in plasma during conditioning chemotherapy for autologous stem cell transplantation in relapsed primary cerebral lymphoma.

Therapeutic drug monitoring for busulfan in plasma during conditioning chemotherapy for autologous stem cell transplantation in relapsed primary cerebral lymphoma has not previously been reported. This case involved a 49-year-old man with relapsed primary cerebral lymphoma who received busulfan (8 mg/kg total dose; 2.67 mg/kg as a 3-hour IV infusion each of days -6 through -4) as part of a multiagent chemotherapy conditioning regimen. Multiple plasma samples were collected for all 3 doses and busulfan was quantified by liquid chromatography tandem mass spectrometry. A 1-compartment model was individually fitted to the concentration-time data for each dose. Clearance decreased across the 3 days of treatment (4.84, 4.06, and 3.04 mL/min/kg, respectively), whereas at the same times half-life increased (2.64, 3.18, and 4.17 hours, respectively), as did area under the plasma concentration-time curve0-infinity (9170, 10,900, and 14,600 microg h/L, respectively). Volume of distribution was similar across this time (1-1.1 L/kg). Indices of both renal and hepatic function did not indicate any significant diminution in likely clearance capacity for busulfan. There was also no compelling evidence for drug interactions that could decrease clearance. We conclude that therapeutic drug monitoring should be recommended for future cases of this rare disease, with a view to developing a target-concentration intervention strategy and improving outcomes.

Assessment of infant dose through milk in a lactating woman taking amisulpride and desvenlafaxine for treatment-resistant depression.

This study presents the case of a 35-year-old breastfeeding mother who delivered her fourth child 5 months previously and was prescribed 100 mg amisulpride twice daily and 250 mg desvenlafaxine in the morning for treatment-resistant depression. Arriving at this regimen took approximately 2 months postbirth. Because she was keen to continue breastfeeding her infant, and published data on the use of amisulpride and desvenlafaxine were very limited, the clinical team sought assistance from the therapeutic drug monitoring laboratory to quantify infant dose-exposure to guide consideration of continuing breastfeeding. A sampling schedule for milk and plasma from mother and plasma from her infant was agreed and drug concentrations were measured by high-performance liquid chromatography. Absolute (theoretic) infant dose (µg/kg/d) was calculated as the product of the average concentration in milk and an assumed milk intake of 0.15 L/kg/day (294 mg/kg/day for desvenlafaxine and 183 mg/kg/day for amisulpride), and relative infant dose was estimated as absolute infant dose expressed as a percentage of the maternal dose in µg/kg/day (7.8% for desvenlafaxine and 6.1% for amisulpride). Consistent with the infant being partially breastfed, the ratio of drug in the infant's plasma to that in mother's plasma was lower at 1.7% for desvenlafaxine and 3.9% for amisulpride. A pediatric assessment of the infant found achievement of expected developmental progress for age and no detectable drug-related adverse effects. Assessing the safety of breastfeeding was difficult because it involved simultaneous use of two drugs for which there was limited previous experience. However, after discussion of the infant dose-exposure data and lack of adverse effects, the mother elected to continue partial breastfeeding for the next few months. The clinical team plans a reassessment of the infant's progress in 3 months.