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Kenneth Ilett

The University of Western Australia, School of Medicine and Pharmacology, Emeritus

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Papers by Kenneth Ilett

Optimal antimalarial dose regimens for sulfadoxine-pyrimethamine with and without azithromycin in pregnancy based on population pharmacokinetic modelling

Antimicrobial agents and chemotherapy, May 27, 2017

Optimal dosing of sulfadoxine-pyrimethamine (SP) as intermittent preventive treatment in pregnanc... more Optimal dosing of sulfadoxine-pyrimethamine (SP) as intermittent preventive treatment in pregnancy remains to be established, particularly when co-administered with azithromycin (AZI). To further characterize SP pharmacokinetics in pregnancy, plasma concentration-time data from 45 non-pregnant and 45 pregnant women treated with SP-AZI (n=15 in each group) and SP-chloroquine (n=30 in each group) were analyzed. Population non-linear mixed effects 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%, 99%) and NASDOX (46%). Co-administration 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 publi...

Estimation of infant dose and exposure to pethidine and norpethidine via breast milk following patient-controlled epidural pethidine for analgesia post caesarean delivery

International journal of obstetric anesthesia, 2011

There is no information about the distribution of pethidine into breast milk and/or exposure of t... more There is no information about the distribution of pethidine into breast milk and/or exposure of the breastfed infant during pethidine patient-controlled epidural analgesia after caesarean delivery. We conducted an observational study among 20 women. The mean (95% confidence interval) pethidine dose administered was 670 (346-818) mg over 41 (35-46) h. Maternal plasma and milk and neonatal plasma were collected near the time of pethidine cessation and 6h later. Absolute and relative infant doses via milk and infant exposure were calculated. Infant behaviour was assessed using the Neurologic and Adaptive Capacity Score. At first and second sampling times, mean absolute infant doses for pethidine were 20 (14-27) μg/kg/day and 10 (7-13) μg/kg/day, while mean relative infant doses were 0.7 (0.1-1.4)% and 0.3 (0.1-0.5)% respectively. Similar values for norpethidine (expressed as pethidine equivalents) were 21 (16-26) μg/kg/day and 22 (12-32) μg/kg/day; and 0.7 (0.3-1)% and 0.6 (0.2-1)% res...

Population PK modeling and simulation based on fluoxetine and norfluoxetine concentrations in milk: A milk concentration-based prediction model

Br J Clin Pharmacol, 2014

Population pharmacokinetic (pop PK) modelling can be used for PK assessment of drugs in breast mi... more 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).

A pilot study of newer antidepressant concentrations in cord and maternal serum and possible effects in the neonate

The International Journal of Neuropsychopharmacology, 2004

Antidepressants are often used antenatally, and placental transfer may lead to adverse effects (t... more Antidepressants are often used antenatally, and placental transfer may lead to adverse effects (toxicity) in the neonate. Pregnant women taking fluoxetine (n=4), sertraline (n=4), paroxetine (n=2) or venlafaxine (n=1) in the last trimester were studied. Maternal and cord sera were collected at delivery and infant serum on day 5 after birth for measurement of antidepressant concentrations. Neonatal Abstinence Scores (NAS) were measured in the infants on days 1-3 after birth. In maternal serum, median drug concentrations were: fluoxetine (96 mg/l), norfluoxetine (110 mg/l), sertraline (11 mg/l), desmethylsertraline (38 mg/l), paroxetine (mean 12 mg/l), venlafaxine (220 mg/l), and O-desmethylvenlafaxine (392 mg/l). Corresponding median values in cord serum were: fluoxetine (65 mg/l), norfluoxetine (81 mg/l), sertraline (10 mg/l), desmethylsertraline (27 mg/l), paroxetine (mean 6 mg/l), venlafaxine (232 mg/l), and O-desmethylvenlafaxine (406 mg/l). Corresponding median cord :maternal concentration ratios were 0.67 for fluoxetine and 0.72 for norfluoxetine, 0.67 for sertraline and 0.63 for desmethylsertraline, 0.52 (mean) for paroxetine, and 1.1 and 1.0 for venlafaxine and O-desmethylvenlafaxine respectively. The neonates of two patients taking fluoxetine had high NAS. Only fluoxetine and norfluoxetine were detected in infant serum. Our data show substantial placental transfer of antidepressants, but only fluoxetine persisted in the infant's serum. Neonatal toxicity may be associated with serotonin re-uptake blockade, and also be influenced by neonatal clearance.

Olanzapine excretion in human breast milk: estimation of infant exposure

The International Journal of Neuropsychopharmacology, 2002

Newer antipsychotic drugs offer significant clinical advantages for the treatment of psychosis. I... more Newer antipsychotic drugs offer significant clinical advantages for the treatment of psychosis. In particular for the treatment of postpartum disorders newer agents may be suited due to their favourable side-effect profiles. Of concern is the passage of the drugs into breast milk and what potential risks this poses for an infant who is breastfed. The excretion of olanzapine into the breast milk of five lactating women with postpartum psychosis was examined in this study. Nine pairs of plasma and breast-milk samples were collected and the concentration of olanzapine determined by high-performance liquid chromatography. Single-point milk-toplasma ratios were calculated and ranged from 0n2 to 0n84 with a mean of 0n46. The median relative infant dose was 1n6 % (range 0-2n5 %) of the weight-adjusted maternal dose. During the study period, there were no apparent ill effects on the infant as a consequence of exposure to these doses of olanzapine. As with other antipsychotic drugs this study demonstrates that olanzapine passes into breast milk. The long-term effects of exposure in infants exposed to olanzapine requires further investigation.

Transfer of dexamphetamine into breast milk during treatment for attention deficit hyperactivity disorder

British Journal of Clinical Pharmacology, 2007

What is already known about this subject • There are presently no published data on dexamphetamin... more What is already known about this subject • There are presently no published data on dexamphetamine transfer into breast milk or on its effects in the breast-fed infant. What this study adds • We have provided quantitative data on the absolute and relative infant doses of dexamphetamine for the breast-fed infant. • We have also documented a lack of overt adverse effects in breast-fed infants despite measurable dexamphetamine concentrations in the infants' plasma. • Hence we now make recommendations for infant safety and monitoring when mothers taking the drug wish to breastfeed. Aims To investigate dexamphetamine transfer into milk, infant doses and effects in the breast-fed infant. Methods Four women taking dexamphetamine, and their infants were studied. Results The median maternal dexamphetamine dose was 18 mg day − 1 (range 15-45 mg day − 1). Median (interquartile range) descriptors were 3.3 (2.2-4.8) for milk/plasma ratio, 21 µ g kg − 1 day − 1 (11-39) for absolute infant dose and 5.7% (4-10.6%) for relative infant dose. No adverse effects were seen. In three infants tested, dexamphetamine in plasma was undetected in one (limit of detection 1 µ g l − 1) and present at 18 µ g l − 1 and 2 µ g l − 1 in the other two. Conclusion Dexamphetamine readily transfers into milk. The relative infant dose was < 10% and within a range that is generally accepted as being 'safe' in the shor t term.

Transfer of methylamphetamine and amphetamine into breast milk following recreational use of methylamphetamine

British Journal of Clinical Pharmacology, 2009

Transfer of chloroquine and desethylchloroquine across the placenta and into milk in Melanesian mothers

British Journal of Clinical Pharmacology, 2008

Absolute infant dose. Tlast sample (mg.days kg-1) 568 (142, 865) 232 (88, 454) Relative infant do... more

Excretion of diazepam and its metabolites in human milk during withdrawal from combination high dose diazepam and oxazepam

British Journal of Clinical Pharmacology, 1990

The excretion of diazepam, N-desmethyldiazepam, temazepam and oxazepam in breast milk was studied... more The excretion of diazepam, N-desmethyldiazepam, temazepam and oxazepam in breast milk was studied during withdrawal of a 22-year-old patient from combined high dose diazepam and oxazepam therapy. Concentrations of these benzodiazepines in plasma from both the woman and her nursing infant (1 year old) were also documented. Diazepam, N-desmethyldiazepam, temazepam and oxazepam were found in the maternal plasma and milk with mean milk: plasma ratios of 0.2, 0.13, 0.14 and 0.10 respectively. It was calculated on a mg kg-1 basis that the infant received some 4.7% of the maternal dose. Diazepam could not be detected in the infant's plasma, but low levels of N-desmethyldiazepam (20 and 21 ,ug 1-1), temazepam (7 ,ug 1-1) and oxazepam (7.5 and 9.6 ,ug 1-1) were present. The infant showed no overt physical or mental symptoms of benzodiazepine intoxication.

Pseudoephedrine: effects on milk production in women and estimation of infant exposure via breastmilk

British Journal of Clinical Pharmacology, 2003

Aims To assess the effects of pseudoephedrine on breast blood flow, temperature and milk producti... more Aims To assess the effects of pseudoephedrine on breast blood flow, temperature and milk production, and to estimate the likely infant dose during breastfeeding. Methods Eight lactating women (mean age 35 years and weight 69 kg) participated in a single-blind randomized crossover study of 60 mg pseudoephedrine hydrochloride vs placebo. Breast blood flow and surface temperature were measured from 0 to 4 h following the dose, and change in plasma prolactin was measured as the difference between predose and 1 h postdose concentrations. Milk production was measured for 24 h following placebo and pseudoephedrine. Infant dose of pseudoephedrine for a 60-mg dose administered four times daily to the mother was quantified as the product of average steady-state drug concentration in milk and an estimated milk production rate of 0.15 l kg-1 day-1 and expressed relative to the maternal weight-adjusted dose. Results There were no physiologically significant changes in breast blood flow or temperature between the placebo and pseudoephedrine periods. The mean change in plasma prolactin was slightly (13.5%), but not significantly lower (t = 1.245, P = 0.253) after pseudoephedrine (1775 mU l-1) compared with placebo (2014 mU l-1). However, the mean milk volume was reduced by 24% from 784 ml day-1 in the placebo period to 623 ml day-1 in the pseudoephedrine period (difference between means 161 ml day-1 (95% CI: 63, 259 ml day-1); t = 3.9, P = 0.006). Assuming maternal intake of 60 mg pseudoephedrine hydrochloride four times daily, the estimated infant dose of pseudoephedrine was 4.3% (95% CI, 3.2, 5.4%) of the weight-adjusted maternal dose. Conclusions A single dose of pseudoephedrine significantly reduced milk production. This effect was not attributable to changes in blood flow, but depression of prolactin secretion may be a contributing factor. At the maximum recommended pseudoephedrine doses, the calculated infant dose delivered via milk was < 10% of the maternal dose, and is unlikely to affect the infant adversely. The ability of pseudoephedrine to suppress lactation suggests a novel use for the drug.

Use of a sparse sampling study design to assess transfer of tramadol and its O-desmethyl metabolite into transitional breast milk

British Journal of Clinical Pharmacology, 2008

Birth weight (kg) 3.4 (3.3-3.5)* 3.4 (3.3-3.5)* Apgar score 1 min 9 (9, 10) † 9 (9, 10) † Apgar s... more Birth weight (kg) 3.4 (3.3-3.5)* 3.4 (3.3-3.5)* Apgar score 1 min 9 (9, 10) † 9 (9, 10) † Apgar score 5 min 9 (9, 10) † 9 (9, 10) † Assessment day post birth 4 (3, 4) † 3 (2, 4) † Neurologic and Adaptive Capacity Score (total) 36 (33, 38) † ‡ 37 (33, 40) † ‡ Neurologic score component 28 (26, 29) † ‡ 27 (26, 30) † ‡ Adaptive capacity score component 9 (8, 10) † ‡ 10 (8, 10) † ‡ *mean (95% CI), †median (IQR), ‡n = 67 (data for four infants lost, while four infants were not tested because they were in the Special Care Nursery for prematurity (3) or ventilation (1)). Neurologic and Adaptive Capacity Score range 0-40, composed of neurologic score range 0-30 and adaptive capacity score range 0-10. rac-Tramadol and rac-O-desmethyltramadol in breast milk

Multiple dose study of interactions between artesunate and artemisinin in healthy volunteers

British Journal of Clinical Pharmacology, 2001

Aims To investigate whether coadministration of the antimalarials artesunate and artemisinin alte... more Aims To investigate whether coadministration of the antimalarials artesunate and artemisinin alters the clearance of either drug. Methods Ten healthy Vietnamese males (Group AS) were randomized to receive a single dose of 100 mg oral artesunate (pro-drug of dihydroartemisinin) on day x5 and then once daily for 5 consecutive days (days 1±5). Oral artemisinin (500 mg) was coadministered on days 1 and 5. Another 10 subjects (Group AM) were given 500 mg oral artemisinin on day x5 and then further doses on days 1±5. Artesunate 100 mg was given on days 1 and 5. Artemisinin and dihydroartemisinin plasma concentrations on days x5, 1 and 5 were quanti®ed by h.p.l.c. with on-line postcolumn derivatization and u.v. detection. Results In Group AS, dihydroartemisinin oral clearance values (mean (95% CI)) were similar on day 1 (32 (22, 47)) l h x1 and day 5 (38 (28, 51)) l h x1 of daily artesunate administration but these mean values were approximately three fold higher compared with day x5 after a single dose (95 (56, 159)). In this group, artemisinin oral clearance increased from 196 (165, 232) l h x1 on day 1±315 (241, 410) l h x1 on day 5. In Group AM, dihydroartemisinin oral clearance on day 1 was 39 (34, 46) l h x1 and increased 1.6 fold to 64 (48, 85) l h x1 on day 5. In this group, artemisinin oral clearance increased sequentially (1.5 and 4.7 fold, respectively) from 207 (151, 285) l h x1 on day x5±308 (257, 368) l h x1 on day 1 and to 981 (678, 1420) l h x1 on day 5. The increase in artemisinin oral clearance between days x5 and 1 (in the absence of artesunate) was similar to that between days 1 and 5 in Group AS subjects who took daily artesunate. Dihydroartemisinin was not a signi®cant metabolite of artemisinin. Conclusions Artesunate (dihydroartemisinin) did not alter the elimination of artemisinin. However, dihydroartemisinin elimination was inhibited by artemisinin. Artemisinin induced its own elimination even 5 days after a single oral dose. There was no evidence for the formation of dihydroartemisinin from artemisinin.

Transfer of the antidepressant mirtazapine into breast milk

British Journal of Clinical Pharmacology, 2007

What is already known about this subject • There is presently only a single case report on mirtaz... more What is already known about this subject • There is presently only a single case report on mirtazapine transfer into breast milk and its effects in the breast-fed infant. What this study adds • Most importantly, we have provided quantitative data on the absolute and relative infant doses of mirtazapine and its active metabolite. • We have also documented a lack of overt adverse effects in the breast-fed infants and low or absent plasma concentrations of mirtazapine in a subset of these infants. • Hence we now know that breast-fed infants are unlikely to be adversely affected when their mothers need to take mirtazapine. Aims To investigate the transfer of mirtazapine and desmethylmirtazapine into milk and to calculate dose to the infant via milk. Methods Plasma and milk samples were obtained from eight breast-feeding women who were taking a median dose of 38 mg mirtazapine per day. Milk/plasma ratio (M/P) and infant doses were estimated by standard methods. The infants were examined clinically and in four infants blood was taken for analysis. Results Mean (95% confidence interval) relative infant doses for mirtazapine and desmethylmirtazapine (n = 8) were 1.5% (0.8, 2.2) and 0.4% (0.2, 0.6) respectively. The mean M/P (area under curve n = 4, single or paired samples n = 3) was 1.1 (0.7,1.5) for mirtazapine and 0.6 (0.5, 0.7) for desmethylmirtazapine. No adverse effects were seen. Mirtazapine was detected (1.5 µ g l − 1) in only one of four infants tested. Conclusion We suggest that mirtazapine use by lactating women is safe for the breast-fed infant. Nevertheless, each decision to breast feed should always be made on the basis of an individual risk/benefit analysis.

Distribution of venlafaxine and its O -desmethyl metabolite in human milk and their effects in breastfed infants

British Journal of Clinical Pharmacology, 2002

Aims To characterize milk/plasma (M/P) ratio and infant dose, for venlafaxine (V) and its O-desme... more Aims To characterize milk/plasma (M/P) ratio and infant dose, for venlafaxine (V) and its O-desmethyl metabolite (ODV), in breastfeeding women taking venlafaxine for the treatment of depression, and to determine the plasma concentration and effects of these drugs in their infants. Methods Six women (mean age 34.5 years, mean weight 84.3 kg) taking venlafaxine (median dose 244 mg day x1 , range 225±300 mg day x1) and their seven infants (mean age 7.0 months, mean weight 7.3 kg) were studied. V and ODV in plasma and milk were measured by high-performance liquid chromatography over a 12 h dose interval at steady-state. Infant exposure was estimated as the product of estimated milk production rate (0.15 l kg x1 day x1) and average drug concentration in milk, normalized to body weight and expressed as a percentage of the weight-adjusted maternal dose. Results Mean M/P AUC values of 2.5 (range 2.0±3.2) and 2.7 (range 2.3±3.2) were calculated for V and ODV, respectively. The mean maximum concentrations (95% CI) of V and ODV in milk were 1161 (95% CI, 588, 1734) mg l x1 and 796 (362, 1230) mg l x1. Mean infant exposure was 3.2% (1.7, 4.7%) for V and 3.2% (1.9, 4.9%) for ODV (as V equivalents). V was detected in the plasma of one out of seven infants studied (5 mg l x1), while ODV was detected in four of the infants, at concentrations ranging from 3 to 38 mg l x1. All of the infants in the study were healthy, as reported by their mothers and/or by clinical examination on the study day. Conclusions The concentrations of V and ODV in breast milk were 2.5 and 2.7 times those in maternal plasma. The mean total drug exposure (as venlafaxine equivalents) of the breastfed infants was 6.4% (5.5±7.3%), which is below the 10% notional level of concern. There were no adverse effects in any of the infants. The data support the use of V in breastfeeding. Nevertheless, since low concentrations of ODV were detected in the plasma of four out of the seven infants studied, we recommend breastfed infants should be monitored closely. Each decision to breast feed should be made as an individual risk:bene®t analysis.

Paroxetine in human milk

British Journal of Clinical Pharmacology, 2001

Aims The primary aims of the study were to estimate the exposure of infants to paroxetine via bre... more Aims The primary aims of the study were to estimate the exposure of infants to paroxetine via breast milk and to determine the maternal milk:plasma ratio (M/P) of paroxetine. Secondary aims were to compare single point and area under the curve (AUC) estimates of M/P, to assess variability of M/P in fore and hind milk, and to compare the observed M/P with that predicted by a model. Methods Two studies were performed. In one study, six nursing mothers who were being treated with paroxetine were studied over a 24 h dose interval at steady-state. The total amount of paroxetine in the milk was measured, which represented the 'dose' to the infant. The M/P AUC was calculated and compared with a predicted value. In the second study, four nursing mothers who were being treated with paroxetine, were studied at steady-state, around a normal infant feeding time. A single plasma sample and a prefeed milk sample were taken approximately 3 h after the morning dose of paroxetine, and a postfeed milk sample taken around 1 h later. The dose received by the infant was estimated from the average milk concentrations of the pre and postfeed samples using standard assumptions, and M/P calculated directly. Plasma concentrations of paroxetine were measured in 8 of the 10 infants in the two studies. Results The mean dose of paroxetine received by the infants in the first study was 1.13% (range 0.5-1.7) of the weight adjusted maternal dose. The mean M/P AUC was 0.39 (range 0.32-0.51). The predicted M/P was 0.22. The mean dose of paroxetine received by the infants in the second study was 1.25% (range 0.38-2.24) of the weight adjusted maternal dose. The mean M/P was 0.96 (range 0.31-3.33) and did not differ between fore and hind milk. The drug was not detected in the plasma of seven of the infants studied and was detected but not quantifiable (<4 mg l −1) in one infant. No adverse effects were observed in any of the infants. Conclusions Measured M/P and estimated infant dose were similar in the two studies, although the range was wider for the single point study. Paroxetine can be considered 'safe' during breast feeding because the dose transferred to the infant is well below the recommended safety limit of 10% of the weight adjusted maternal dose, concentrations in the infants were generally undetectable, and no adverse effects were reported.

Transfer of escitalopram and its metabolite demethylescitalopram into breastmilk

British Journal of Clinical Pharmacology, 2006

Aims To investigate the transfer of escitalopram and its demethyl metabolite into milk, the absol... more Aims To investigate the transfer of escitalopram and its demethyl metabolite into milk, the absolute and relative infant doses via milk and to assess any unwanted effects in the breastfed infant. Methods Multiple samples of blood and milk were obtained over a dose interval at steady state from eight women who were taking escitalopram for postnatal depression. Drug concentrations in plasma and milk were measured by high-per formance liquid chromatography and milk/plasma ratio (M/P AUC), absolute infant dose and relative infant dose were estimated by standard methods. Their breastfed infants were also examined clinically and in five infants a blood sample was taken for drug analysis. Results The median dose taken by the women was 10 mg day − 1. The mean (95% confidence interval) M/P AUC was 2.2 (2.0, 2.4) for escitalopram and 2.2 (1.9, 2.5) for demethylescitalopram. Absolute infant doses were 7.6 µ g kg − 1 day − 1 (5.2, 10.0) for escitalopram and 3.0 µ g kg − 1 day − 1 (2.4, 3.6) for demethylescitalopram. The total relative infant dose for escitalopram plus its demethyl metabolite was 5.3% (4.2, 6.4) as escitalopram equivalents. All of the infants had met normal developmental milestones and no adverse effects were seen. Compared with average maternal plasma concentrations (24 µ g l − 1), the concentrations of the parent drug and its metabolite in plasma from five infants were most commonly below the limit of detection (≤ 3 µ g l − 1). Conclusion The study shows that escitalopram is safe for use during breastfeeding. Because its absolute infant dose is lower than that for an equivalent antidepressant dose of raccitalopram, it may be preferred over rac-citalopram in treating depression in lactating women. Nevertheless, each decision to breastfeed should always be made on the basis of an individual risk:benefit analysis.

Population Pharmacokinetics of Artemether, Lumefantrine, and Their Respective Metabolites in Papua New Guinean Children with Uncomplicated Malaria

Antimicrobial Agents and Chemotherapy, 2011

There are sparse published data relating to the pharmacokinetic properties of artemether, lumefan... more 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 c...

Desbutyl-Lumefantrine Is a Metabolite of Lumefantrine with Potent In Vitro Antimalarial Activity That May Influence Artemether-Lumefantrine Treatment Outcome

Antimicrobial Agents and Chemotherapy, 2011

Desbutyl-lumefantrine (DBL) is a metabolite of lumefantrine. Preliminary data from Plasmodium fal... more 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 dihydroartemisini...

Pharmacokinetics of Chloroquine and Monodesethylchloroquine in Pregnancy

Antimicrobial Agents and Chemotherapy, 2010

In order to determine the pharmacokinetic disposition of chloroquine (CQ) and its active metaboli... more 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 μg·h/liter, P < 0.001) and DECQ (23,073 versus 41,584 μg·h/liter, P < 0.001), reflecting significant di...

Artesunate Suppositories versus Intramuscular Artemether for Treatment of Severe Malaria in Children in Papua New Guinea

Antimicrobial Agents and Chemotherapy, 2006

Drug treatment of severe malaria must be rapidly effective. Suppositories may be valuable for chi... more Drug treatment of severe malaria must be rapidly effective. Suppositories may be valuable for childhood malaria when circumstances prevent oral or parenteral therapy. We compared artesunate suppositories ( n = 41; 8 to 16 mg/kg of body weight at 0 and 12 h and then daily) with intramuscular (i.m.) artemether ( n = 38; 3.2 mg/kg at 0 h and then 1.6 mg/kg daily) in an open-label, randomized trial with children with severe Plasmodium falciparum malaria in Papua New Guinea (PNG). Parasite density and temperature were measured every 6 h for ≥72 h. Primary endpoints included times to 50% and 90% parasite clearance (PCT 50 and PCT 90 ) and the time to per os status. In a subset of 29 patients, plasma levels of artemether, artesunate, and their common active metabolite dihydroartemisinin were measured during the first 12 h. One suppository-treated patient with multiple complications died within 2 h of admission, but the remaining 78 recovered uneventfully. Compared to the artemether-treated...