Search

AIMS The effect of repeat oral supratherapeutic dosing of the BRAF inhibitor dabrafenib on QTc interval was assessed in patients with BRAF V600-mutant tumours. METHODS Part 1 of this phase 1, multicentre, 2-part study (BRF113773/NCT01738451) assessed safety/tolerability of dabrafenib 225 or 300 mg twice daily (BID) to inform part 2 dosing. Patients in part 2 received dabrafenib-matched placebo on day -1, single-dose dabrafenib 300 mg on day 1, 300 mg BID on days 2 to 7, and 300 mg on day 8 (morning), followed by 24-h Holter electrocardiographic monitoring and pharmacokinetics sample collection each dose day. Pharmacokinetics/pharmacodynamics analysis assessed combined dabrafenib and metabolite effects on QTc interval. RESULTS Part 1 (n = 12) determined supratherapeutic dosing, 300 mg BID, for part 2. Thirty-one patients completed part 2. Mean maximum ΔΔQTcF occurred on day 8, 10 h postdose (2.86 msec; 90% CI, -1.36 to 7.07). Categorical analysis showed no placebo and dabrafenib outliers (increase >60 msec; QTcF >500 msec). Day 1 dabrafenib 300 mg Cmax and AUC(0-∞) were ≈ 2-fold higher than with single-dose 150 mg. Day 8 AUC(0-τ) with 300 mg BID was ≈ 2.7-fold higher than with 150 mg BID. Dabrafenib metabolites showed similar trends. Pharmacokinetics/pharmacodynamics modelling/simulation showed that median QTc increase was

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.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • There are presently no published data on tramadol transfer into breast milk or on its effects in the breastfed infant. WHAT THIS STUDY ADDS • We have provided quantitative data on the absolute and relative infant doses of rac-tramadol and it rac-O-desmethyl metabolite for the breastfed infant. • We have also demonstrated a novel sparse sampling data collection method for investigating infant exposure via milk. AIMS To investigate the transfer of rac-tramadol and its rac-O-desmethyl metabolite into transitional milk, and assess unwanted effects in the breastfed infant. METHODS Tramadol HCl (100 mg six hourly) was administered to 75 breastfeeding mothers for postoperative analgesia on days 2–4 after Caesarian section. Milk and plasma samples were collected after administration of four or more doses. Rac-tramadol and rac-O-desmethyltramadol were measured by high performance liquid chromatography. Milk : plasma ratio (M : P) and infant doses were calculated by standard methods. The behavioural characteristics of the exposed breastfed infants and a matched control group of infants not exposed to tramadol were also studied. RESULTS At steady-state, mean (95% CI) M : P was 2.2 (2.0, 2.4) for rac-tramadol and 2.8 (2.5, 3.1) for rac-O-desmethyltramadol. The estimated absolute and relative infant doses were 112 (102, 122) μg kg−1 day−1 and 30 (28, 32) μg kg−1 day−1, and 2.24% (2.04, 2.44)% and 0.64% (0.59, 0.69)% for rac-tramadol and rac-O-desmethyltramadol, respectively. The exposed infants and control breastfed infants had similar characteristics, including Apgar scores at birth and Neurologic and Adaptive Capacity Scores. CONCLUSIONS The combined relative infant dose of 2.88% at steady-state was low. The similarity of NACS in exposed infants and controls suggests that there were no significant behavioural adverse effects. We conclude that short-term maternal use of tramadol during establishment of lactation is compatible with breastfeeding.

To investigate the transfer of mirtazapine and desmethylmirtazapine into milk and to calculate dose to the infant via milk.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.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 microg l(-1)) in only one of four infants tested.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.

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-performance liquid chromatography and milk/plasma ratio (M/PAUC), 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/PAUC was 2.2 (2.0, 2.4) for escitalopram and 2.2 (1.9, 2.5) for demethylescitalopram. Absolute infant doses were 7.6 µg kg−1 day−1 (5.2, 10.0) for escitalopram and 3.0 µg 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 µg 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 µg 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 rac-citalopram, 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.

Aims To determine the ratio of α : β anomers and the protein binding of dihydroartemisinin (DHA) in vivo. Methods 10-[3H]-DHA was synthesized by reduction of artemisinin with sodium boro-[3H]-hydride and purified with preparative thin layer chromatography. A solution of 3H-DHA (2000 ng in 20 µl) was added to 2 ml whole blood from 15 healthy volunteers and 22 Vietnamese patients with falciparum or vivax malaria. The blood was centrifuged and the plasma stored at −25 °C until analysed by HPLC with radiochromatographic detection. Protein-free ultrafiltrate of the plasma was assayed to determine the free fraction of DHA and the in vivo ratio of α-DHA : β-DHA. Results The DHA fraction unbound (mean ± SD) was 0.068 ± 0.032 in Vietnamese patients with falciparum malaria (n = 17), 0.065 ± 0.009 in Vietnamese patients with vivax malaria (n = 5), 0.117 ± 0.015 in Vietnamese volunteers (n = 7) and 0.092 ± 0.020 in Caucasian volunteers (n = 8). The ratios of α-DHA : β-DHA for the four groups were 6.3 ± 0.9, 6.9 ± 0.8, 6.9 ± 0.6 and 5.4 ± 0.8, respectively. Conclusions DHA is approximately 93% protein-bound in patients with malaria infection and there is a preferential existence in vivo of the α-DHA anomer. Knowledge of this stereochemistry may be valuable in elucidation of the mechanisms of DHA action and/or toxicity, and in the synthesis of new trioxane antimalarials.

Aims To study the population pharmacokinetics of piperaquine after co-administration with dihydroartemisinin in uncomplicated malaria. Methods The disposition of piperaquine was studied in 85 Cambodian patients with uncomplicated falciparum or vivax malaria treated with the piperaquine-dihydroartemisinin coformulation Artekin®. All patients were given Artekin® orally at 0, 6, 24 and 32 h with a total piperaquine dose of 32–35 mg base kg−1. Adults were given tablets while children received either tablets or a dispersible granule formulation. Patients underwent either intensive (17–19 samples) or sparse (2–5 samples) blood sampling schedules over 35 days and clinical/parasitological follow-up over > 28 days. Piperaquine in plasma was quantified by high performance liquid chromatography. Results All patients achieved fever clearance within 24 h and parasite clearance within 72 h. The 28-day cure rate was 97% in adults and 98% in children. A covariate-free two-compartment population model with first-order absorption and elimination gave the most robust representation of the plasma concentration-time data in both adults and children. In adults (n = 38), the median (interquartile range) derived pharmacokinetic descriptors CL/F, Vss/F and t1/2,z were 0.9 l h−1 kg−1 (0.79–1.02 l h−1 kg−1), 574 l kg−1(371–711 l kg−1) and 23 days (19–28 days), respectively. In children (n = 47), corresponding values were 1.8 l h−1 kg−1 (1.29–2.3 l h−1 kg−1), 614 l kg−1 (332–1205 l kg−1) and 14 days (10–18 days), respectively. Conclusions Piperaquine is a highly lipid-soluble drug with a large Vss/F, long t1/2,z and a clearance that is markedly higher in children than in adults.

Aims To assess the haemodynamic, electrocardiographic and glycaemic effects of piperaquine-dihydroartemisinin (Artekin®) fixed combination therapy in uncomplicated malaria. Methods Sixty-two Cambodians (32 children and 30 adults) with falciparum or vivax malaria were given Artekin® given as four age-based oral doses over 32 h. Supine and erect blood pressure, the electrocardiographic QT interval and plasma glucose were measured before treatment and then at regular intervals during a 4-day admission period as part of efficacy and safety monitoring. QT intervals were rate-corrected (QTc) using Bazett's formula. Results Artekin® therapy was well tolerated and all patients responded to treatment. Average parasite and fever clearance times were 19 and 12 h, respectively. The pretreatment mean fall in systolic blood pressure on standing was 8 ± 6 mmHg and 6-hourly measurements over 72 h showed no significant change (P = 0.48). There was a significant lengthening of the mean QTc to a maximum of 11 ms0.5 (95% confidence interval 4–18 ms0.5) relative to baseline at 24 h (P = 0.003). The maximal QTc prolongation observed in any patient was 53 ms0.5. There was a mean 0.4 mmol l−1 reduction in the post-absorptive plasma glucose during the first 48 h but no episodes of hypoglycaemia (plasma glucose

There have been numerous anecdotal reports that pseudoephedrine use results in decreased milk production (Anderson 2000). This study was carried out to determine milk production, plasma prolactin levels, blood flow to the breast, and milk levels of pseudoephedrine following a maternal dose of 60 mg. Pseudoephedrine is a sympathomimetic amine (alpha-adrenoceptor agonist) that enjoys wide use as a nasal mucous membrane and sinus decongestant. The drug has been detected in the milk of three nursing mothers (at 3, 3, and 18 months of lactation) after ingestion of a single dose of a combined pseudoephedrine HC1 60 mg /triprolidine HC1 2.5 mg tablet (Findlay et al. 1984). The average concentration in milk over 24 hours was 264 µg/L. Although milk production was not measured, it was calculated that this would correspond to a relative infant dose of around 5% of the weight-adjusted maternal dose.

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−1, range 225–300 mg day−1) 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−1day−1) and average drug concentration in milk, normalized to body weight and expressed as a percentage of the weight-adjusted maternal dose. Results Mean M/PAUC 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) µg l−1 and 796 (362, 1230) µg l−1. 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 µg l−1), while ODV was detected in four of the infants, at concentrations ranging from 3 to 38 µg l−1. 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:benefit analysis.

Aims To obtain pharmacokinetic data for artesunate (ARTS) and its active metabolite dihydroartemisinin (DHA) following i.m. ARTS and rectal DHA administration.

Results For immature milk (n=8) the M/PAUC for R-methadone was 0.68 (95% CI 0.48, 0.89) and for S-methadone 0.38 (0.26, 0.50). For mature milk (n=2) the M/PAUCs for R-methadone were 0.39 and 0.54 and for S-methadone 0.24 and 0.30, respectively. The estimated doses of R- and S-methadone that would be received by the infant via immature milk were 3.5% (2.05, 5.03%) and 2.1% (1.3, 2.8%), respectively, of the maternal dose (assuming 50% of each enantiomer in the dose). The relative infant dose for R- plus S-methadone together was 2.8% (1.7, 3.9%). Conclusions Breastfeeding during medium to high dose methadone appears to be ‘safe’ according to conventional criteria because the dosage is

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 −5 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 −5 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 −5, 1 and 5 were quantified 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−1 and day 5 (38 (28, 51)) l h−1 of daily artesunate administration but these mean values were approximately three fold higher compared with day −5 after a single dose (95 (56, 159)). In this group, artemisinin oral clearance increased from 196 (165, 232) l h−1 on day 1–315 (241, 410) l h−1 on day 5. In Group AM, dihydroartemisinin oral clearance on day 1 was 39 (34, 46) l h−1 and increased 1.6 fold to 64 (48, 85) l h−1 on day 5. In this group, artemisinin oral clearance increased sequentially (1.5 and 4.7 fold, respectively) from 207 (151, 285) l h−1 on day −5–308 (257, 368) l h−1 on day 1 and to 981 (678, 1420) l h−1 on day 5. The increase in artemisinin oral clearance between days −5 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 significant 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.

Aims To obtain comprehensive bioavailability data for artesunate (ARTS) and its active metabolite dihydroartemisinin (DHA) following their separate oral administration to Vietnamese volunteers and to patients with acute, uncomplicated falciparum malaria. Methods Volunteers were randomized to receive either i.v. ARTS (120 mg) followed by oral ARTS (150 mg) 8 h later (Group 1, n = 10), or i.v. ARTS (120 mg) followed by oral DHA (120 mg) 8 h later. Patients, also received oral ARTS (150 mg; Group 3, n = 8) or DHA (120 mg; Group 2, n = 7), in a randomized cross-over study design. Multiple blood samples were collected after each administration and plasma ARTS and/or DHA concentrations were determined by h.p.l.c. Pharmacokinetic descriptors were obtained from noncompartmental analysis and bioavailability was calculated from AUC data. In the patients, the time to 50% parasite clearance (PCT50) and fever clearance time (FCT) also were measured. Results In Group 1 (volunteers), the mean (95% CI) absolute bioavailability of oral ARTS was 80% (62,98%), while in Group 2 (volunteers), the bioavailability of oral DHA was 45% (34,56%). In the patients (Group 3), the bioavailability of oral DHA relative to oral ARTS was 88% (49,127%). The median PCT50 and FCT were 2.3 and 28 h, respectively. Conclusions The study shows that the absolute bioavailability of DHA was significantly lower than that for ARTS in healthy volunteers. The bioavailability of ARTS in volunteers was consistent with previous studies in patients with uncomplicated falciparum malaria. The dose-normalized Cmax and AUC(0,∞) for DHA were significantly greater in patients with falciparum malaria than in healthy volunteers. The high relative bioavailability of DHA in the patients may have been due to lower first-pass clearance. We conclude that, for the treatment of malaria, DHA is likely to be a suitable oral substitute for ARTS. Based on our mean AUC measurements, it appears that equal doses of DHA and ARTS (mg basis) should give equivalent systemic exposure to bioactive DHA in uncomplicated falciparum malaria.

Aims To characterize milk/plasma (M/P) ratio and infant dose, for citalopram and demethylcitalopram, in breast-feeding women taking citalopram for the treatment of depression, and to determine the plasma concentration and effects of these drugs in their infants. Methods Seven women (mean age 30.6 years) taking citalopram (median dose 0.36 mg kg−1 day−1) and their infants (mean age 4.1 months) were studied. Citalopram and demethylcitalopram in plasma and milk were measured by high-performance liquid chromatography over a 24 h dose interval. Infant exposure was estimated (two separate methods) as the product of milk production rate and drug concentration in milk, normalized to body weight and expressed as a percentage of the weight-adjusted maternal dose. Results Mean M/PAUC values of 1.8 (range 1.2–3) and 1.8 (range 1.0–2.5) were calculated for citalopram and demethylcitalopram, respectively. The mean maximum concentrations of citalopram and demethylcitalopram in milk were 154 (95% CI, 102–207) µg l−1 and 50 (23–77) µg l−1. Depending on the method of calculation, mean infant exposure was 3.2 or 3.7% for citalopram and 1.2 or 1.4% for demethylcitalopram. Citalopram (2.0, 2.3 and 2.3 µg l−1) was detected in three of the seven infants. Demethylcitalopram (2.2 and 2.2 µg l−1) was detected in plasma from two of the same infants. No adverse effects were seen in the infants, all were within appropriate percentile limits for weight and all had normal Denver developmental quotients. Conclusions The mean combined dose of citalopram and demethylcitalopram (4.4–5.1% as citalopram equivalents) transmitted to infants via breast milk is below the 10% notional level of concern. Plasma concentrations of these drugs in the infants were very low or absent and there were no adverse effects. These data support the safety of the use of citalopram in breast feeding women. Nevertheless, each decision to breast feed should always be made as an individual risk:benefit analysis.

Aims Pharmacokinetic variability is likely to be a significant factor contributing to the interindividual differences in dose requirements, anti-inflammatory response and side-effects with inhaled corticosteroids (ICS), but there is limited information about the disposition of ICS during regular dosing with a pressurized metered dose inhaler (pMDI). This study uses a mixed effects modelling approach to quantify and compare the interindividual variability in pharmacokinetics of epimeric budesonide (BUD) and fluticasone propionate (FP) after repeat-dose inhalation. Methods This pharmacokinetic substudy was part of a previously published open-label, randomised, placebo-controlled, 7-period crossover study to evaluate the short-term effects on plasma cortisol levels of inhaled BUD (400, 800, 1600 µg twice daily) and FP (375, 750, 1000 µg twice daily) via pMDI in a group of healthy male volunteers. On the fifth day of each high-dose treatment period (BUD 1600 µg twice daily and FP 1000 µg twice daily), venous blood samples were collected in nine subjects prior to the last dose and at 15 min, 30 min, 1, 2, 4, 6 and 8 h postdose for measurement of plasma drug concentrations to determine the pharmacokinetics of epimeric BUD and FP following inhalation. Non-compartmental analysis and a mixed effects model were used to characterize the disposition profiles. Results Both drugs had a rapid absorption half-life (BUD 10 min vs FP 11.3 min), but quite different elimination half-lives (BUD 2.4 h vs FP 7.8 h). Although there were intraindividual differences in the handling of the 22R-and 22S-epimers of BUD, there were no consistent pharmacokinetic differences between the two enantiomers in the group as a whole. Consistent with previous reports of FP’s higher volume of distribution (V) and lower systemic bioavailability (F), the V/F ratio was lower for BUD than FP (498 l vs 8100 l). The parameter with the greatest interindividual variability for both BUD and FP was the rate of systemic absorption from the lung. Conclusions This is the first report describing the pharmacokinetics of epimeric BUD and FP after repeat dose inhalation via pMDI. Three observations may be of clinical relevance: (1) there is considerable intersubject variability in the rate of absorption of both drugs from the lung; (2) in some individuals there was a long t½,z for BUD, resulting in higher and more sustained plasma drug levels in the 4–12 h postdose period than would be predicted from single-dose pharmacokinetic data; and (3) there is evidence of diurnal variation in FP pharmacokinetics, with higher-than-expected plasma drug concentrations in the morning compared with the evening.

Aims This was a pilot study of the use of a clinical pharmacist as a therapeutics adviser (academic detailer) to modify antibiotic prescribing by general practitioners. Methods Following a visit by the adviser (March-May), 112 general practitioners were recruited and randomised to control or active groups. A panel of experts prepared a best practice chart of recommended drugs for upper and lower respiratory tract infections, otitis media and urinary tract infections. The adviser made a 10–15 min visit to each prescriber in the active group (June–July), gave them the chart and discussed its recommendations briefly. Doctors in the control group were not visited nor given the chart. Prescription numbers for all prescribers were obtained from the Commonwealth Health Insurance Commission for the pre(March-May) and postdetailing (August–September) periods using a three month lag time for data collection. Data for total numbers of prescriptions and for selected individual antibiotics used in these two periods were analysed using nonparametric statistics. Results Prescribing patterns were similar for the control and active groups in the predetailing period. For both groups, there were significant (P

Aims To characterize milk/plasma (M/P) ratio and infant dose, for fluoxetine and norfluoxetine, in breast-feeding women taking fluoxetine for the treatment of depression, and to determine the plasma concentration of these drugs in their infants. Methods Fourteen women (mean age 32.2 years) taking fluoxetine (mean dose 0.51 mg kg−1 day−1 ) and their infants (mean age 3.4 months) were studied. Fluoxetine and norfluoxetine in plasma and milk were measured by high-performance liquid chromatography over a 24 h dose interval in four patients, and by single point data collection in 10 patients. Infant exposure was estimated as the product of estimated milk production, 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 values of 0.68 (95% CI 0.52–0.84) and 0.56 (95% CI 0.35–0.77) were calculated for fluoxetine and norfluoxetine, respectively. Mean total infant exposure (fluoxetine equivalents) was estimated to be 6.81% (range 2.15–12%) of the weight-adjusted maternal dose of fluoxetine. Contributions from fluoxetine and norfluoxetine were approximately equal. Fluoxetine (range 20–252 μg l−1 ) was detected in five of the nine infants from whom samples were collected, and norfluoxetine (range 17–187 μg l−1 ) was detected in seven of the nine infants. The highest of these concentrations was about 70% of the maternal plasma concentrations. Conclusions The mean combined dose of fluoxetine and norfluoxetine transmitted to infants via breast milk is below the 10% notional level of concern. However, there was considerable interpatient variability in estimated infant dose and in some of the patients, the dose was >10%. Further, since adverse effects have been observed in breast-fed infants, careful monitoring of the infants is mandatory. Neonates exposed to these drugs in utero had higher concentrations of fluoxetine and norfluoxetine and are at greater risk of adverse effects.

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/PAUC 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/PAUC 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 diVer 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 (

Aims To characterise milk/plasma (M/P) ratio and infant exposure, for sertraline and N-desmethylsertraline, in breast-feeding women taking sertraline for the treatment of depression. Methods Eight women (mean age 28 years) taking sertraline (1.05 mg kg−1 day−1 ) and their infants (mean age 5.7 months) were studied. Sertraline and N-desmethylsertraline in plasma and milk were measured by high-performance liquid chromatography over a 24 h dose interval at steady-state. M/P values were estimated from area under the plasma and milk concentration-time curves. All milk produced was collected over the dose interval. Infant exposure was estimated as the product of actual or estimated milk production, and average drug concentration in milk, normalized to body weight and expressed as a percentage of the weight-adjusted maternal dose. Results Mean milk production was 321 ml day−1 (range 34–974 ml). Mean M/P values of 1.93 and 1.64 were calculated for sertraline and N-desmethylsertraline respectively. Infant exposure estimated from actual milk produced was 0.2% and 0.3% of the weight-adjusted maternal dose for sertraline and N-desmethylsertraline (as sertraline equivalents) respectively. When calculated from estimated milk production (0.15 l kg−1 day−1 ), infant exposure was significantly greater (P

Aims To characterise the transfer of venlafaxine (V) and its O-desmethyl metabolite (ODV) into human milk by measuring milk/plasma (M/P) ratio, and to estimate the likely dose received by a breast-fed infant. Methods Milk and plasma samples were collected from three lactating women who were taking venlafaxine for depression, and were at steady-state. In two of the patients, venous blood and milk samples were collected 0, 1, 2, 3, 4, 6, 8 and 12 h post dose, while in the third patient a single pair of blood and milk samples was obtained 0.83 h post dose. A plasma sample was obtained from each of their infants. V and ODV were measured in plasma and milk by high performance liquid chromatography. M/P was calculated and infant dose estimated as drug concentration in milk×a milk intake of 0.15 l kg−1 day−1, relative to the weight-adjusted maternal dose. Results Mean M/P for V was 4.1 (range 2.8–4.8) and 3.1 for ODV (range 2.8–3.8). The mean total infant dose (as V equivalents) was 7.6% (range 4.7–9.2%) of the maternal weight-adjusted dose, with approximately equal amounts of V (3.5%) and ODV (4.1%) in the dose. ODV (median 100 μg l−1 ) was detected in the plasma of all three infants. The infants were healthy and showed no acute adverse effects. Conclusions These preliminary data show that the total dose of V and ODV ingested by breast-fed infants can be as high as 9.2% of maternal intake. Moreover there were measurable concentrations of ODV in the infants’ plasma. We recommend that exposed infants should be observed closely.

Aims Methadone is widely used in maintenance programs for opioid-dependent subjects. The aims of the study were to quantify the distribution and excretion of methadone in human milk during the early postnatal period and to investigate exposure of breast fed infants to the drug. Methods Blood and milk samples were obtained from 12 breast feeding women who were taking methadone in daily doses ranging from 20-80 mg (0.3-1.14 mg kg-1). Blood was also obtained from eight of their infants. Methadone concentration in these samples was quantified by h.p.l.c. The infants were observed for withdrawal symptoms. Results The mean (95% CI) milk/plasma ratio was 0.44 (0.24-0.64). Exposure of the infants, calculated assuming an average milk intake of 0.15 l kg-1 day-1 and a bioavailability of 100% was 17.4 (10.8-24) microg kg-1 day-1. The mean infant dose expressed as a percentage of the maternal dose was 2.79 (2.07-3.51)%. Methadone concentrations in seven infants were below the limit of detection for the h.p.l.c. assay procedure, while one infant had a plasma methadone concentration of 6.5 microg l-1. Infant exposure to methadone via human milk was insufficient to prevent the development of a neonatal abstinence syndrome which was seen in seven (64%) infants. No adverse effects attributable to methadone in milk were seen. Conclusions We conclude that exposure of breast fed infants to methadone taken by their mothers is minimal and that women in methadone maintenance programs should not be discouraged from breast feeding because of this exposure.

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.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.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.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).

1. The mechanism of the interaction between ciprofloxacin and theophylline was investigated in nine healthy subjects. 2. Subjects were given a single oral dose of theophylline (3.4 mg kg-1), before and after 60 h of ciprofloxacin therapy at a dose of 500 mg twice daily. 3. Ciprofloxacin reduced the oral clearance of theophylline by 19% (-7.73 +/- 6.42 ml kg-1 h-1 (95% confidence limits -12.66, -2.79)). Some subjects (group A, n = 4) showed little decrease in clearance (mean 4.4%; -1.6 +/- 0.7 ml kg-1 h-1 (-2.6, 0.5)), whereas others (group B, n = 5) showed a marked decrease (mean 30%; -12.7 +/- 3.7 ml kg-1 h-1 (-17.2, -8.1)). 4. Comparing groups A and B, the decrease in oral clearance of theophylline in group B could not be ascribed to differences in the AUC of ciprofloxacin. Group A subjects showed only slight inhibition of 1-demethylation (-12.8 +/- 5.5% (-21.5, -4.0)), while group B subjects showed a significantly greater inhibition of 1-demethylation (-49.9 +/- 9.8% (-62.1, -37.7)), 3-demethylation (-44.8 +/- 8.6% (-55.4, -34.1)) and 8-hydroxylation (-27.0 +/- 3.7% (-31.6, -22.4)). 5. The results suggest that inter-individual variability in the inhibition of theophylline metabolism by ciprofloxacin can be attributed to inter-individual differences in the level of CYP1A2 expression and/or in the degree of inhibition of hepatic CYP1A2 and CYP3A4. 6. The interaction between ciprofloxacin and theophylline can be clinically significant.(ABSTRACT TRUNCATED AT 250 WORDS)