Enantiomer-specific ketorolac pharmacokinetics in young women, including pregnancy and postpartum period.

Racemic ketorolac clearance (CL) is significantly higher at delivery, but S-ketorolac disposition determines the analgesic effects. The aim of this study was to investigate the effect of pregnancy and postpartum period on enantiomer-specific (S and R) intravenous (IV) ketorolac pharmacokinetics (PKs). Data in women shortly following cesarean delivery (n=39) were pooled with data in a subgroup of these women that was reevaluated in the later postpartum period (postpartum group, n=8/39) and with eight healthy female volunteers. All women received single IV bolus of 30 mg ketorolac tromethamine. Five plasma samples were collected at 1, 2, 4, 6, and 8 hours and plasma concentrations were determined using high performance liquid chromatography. Enantiomer-specific PKs were calculated using PKSolver. Unpaired analysis showed that distribution volume at steady state (Vss, L/kg) for S- and R-ketorolac was significantly higher in women shortly following cesarean delivery (n=31) compared to postpartum group (n=8) or to healthy female volunteers (n=8). CL, CL to body weight, and CL to body surface area (CL/BSA) for S- and R-ketorolac were also significantly higher in women following delivery. In addition, S/R-ketorolac CL/BSA ratio was significantly higher at delivery. Paired PK analysis in eight women shortly following delivery and in postpartum group showed the same pattern. Finally, the simultaneous increase in CL and Vss resulted in similar estimates for elimination half-life in both unpaired and paired analysis. In conclusion, pregnancy affects S-, R-, and S/R-ketorolac disposition. This is of clinical relevance since S-ketorolac (analgesia) CL is even more increased compared to R-ketorolac CL, and S/R-ketorolac CL ratio is higher following delivery compared to postpartum period or to healthy female volunteers.

Low but inducible contribution of renal elimination to clearance of propylene glycol in preterm and term neonates.

BACKGROUND: Despite limited information being available on the pharmacokinetics of excipients, propylene glycol (PG) is often used as an excipient in both adults and children. The aim of this study is to characterize the renal and hepatic elimination of PG in preterm and term neonates. METHODS: The pharmacokinetic analysis of PG was performed in NONMEM 6.2. on the basis of PG concentrations in plasma and/or urine samples for a total of 69 (pre)term neonates (birth weight 630-3980 g, gestational age 24-41 weeks, postnatal age 1-29 days) who received PG coadministered with intravenous paracetamol (5-10 mg/kg per 6 hours), phenobarbital (5 mg·kg(-1)·d(-1)), or both. To capture the time-dependent trend in the renal excretion of PG, different models based on time after the first dose, urine volume, and creatinine amount in urine were tested. RESULTS: A one-compartment model parameterized in terms of renal clearance, hepatic clearance, and volume of distribution was found to adequately describe the observations in both plasma and urine. After the first dose was administered, the renal elimination of PG was 15% of total clearance, which increased over time to 25% at 24 hours after the first dose of PG. This increase was best described using a hyperbolic function based on time after the first dose. CONCLUSIONS: Renal elimination of PG in (pre)term neonates is low, particularly compared with the reported percentage of 45% in adults, but it may increase with time after the first dose of PG. To study whether this increase is caused by an autoinduced increase in the renal secretion or a reduction of tubular reabsorption of PG, further research is needed.

Developmental pharmacokinetics of propylene glycol in preterm and term neonates.

AIM: Propylene glycol (PG) is often applied as an excipient in drug formulations. As these formulations may also be used in neonates, the aim of this study was to characterize the pharmacokinetics of propylene glycol, co-administered intravenously with paracetamol (800 mg PG/1000 mg paracetamol) or phenobarbital (700 mg PG/200 mg phenobarbital) in preterm and term neonates. METHODS: A population pharmacokinetic analysis was performed based on 372 PG plasma concentrations from 62 (pre)term neonates (birth weight (bBW) 630-3980 g, postnatal age (PNA) 1-30 days) using NONMEM 6.2. The model was subsequently used to simulate PG exposure upon administration of paracetamol or phenobarbital in neonates (gestational age 24-40 weeks). RESULTS: In a one compartment model, birth weight and PNA were both identified as covariates for PG clearance using an allometric function (CL(i) = 0.0849 × {(bBW/2720)(1.69) × (PNA/3)(0.201)}). Volume of distribution scaled allometrically with current bodyweight (V(i) = 0.967 × {(BW/2720)(1.45)}) and was estimated 1.77 times higher when co-administered with phenobarbital compared with paracetamol. By introducing these covariates a large part of the interindividual variability on clearance (65%) as well as on volume of distribution (53%) was explained. The final model shows that for commonly used dosing regimens, the population mean PG peak and trough concentrations range between 33-144 and 28-218 mg l(-1) (peak) and 19-109 and 6-112 mg l(-1) (trough) for paracetamol and phenobarbital formulations, respectively, depending on birth weight and age of the neonates. CONCLUSION: A pharmacokinetic model was developed for PG co-administered with paracetamol or phenobarbital in neonates. As such, large variability in PG exposure may be expected in neonates which is dependent on birth weight and PNA.

Urinary metabolites after intravenous propofol bolus in neonates.

In neonates, propofol mainly undergoes hydroxylation to quinol metabolites with only limited glucuronidation. The aim of this study is to search for covariates of neonatal propofol biotransformation based on 24 h urine collections. In neonates receiving an intravenous propofol bolus for short procedural sedation, urine was collected during 24 h. Urinary propofol metabolites [propofol glucuronide (PG), 1- and 4-quinol glucuronide (QG)] were determined using high-performance liquid chromatography after a dual-step solid phase extraction combined with ultraviolet and fluorescence detection. Propofol metabolites, their contribution to total metabolite elimination and propofol glucuronide/quinol glucuronide (PG/QG) ratio were determined. The impact of continuous [postmenstrual age (PMA), postnatal age (PNA), body weight, propofol dose, creatinaemia] and dichotomous variables [PNA ≤ 7 days (yes/no), PNA ≥ 10 days (yes/no), hyperbilirubinaemia (yes/no), cardiopathy (yes/no)] on PG/QG ratio and on patients with low (≤10 %) vs. high (>10 %) urinary PG recovery were examined. Thirty-two neonates were included. Median total propofol metabolite recovery was 40.95 (2.01-129.81) % with PG/QG ratio 0.44 (0.01-5.93). PNA (dichotomous 7 days as well as 10 days) was a significant covariate of PG/QG ratio. Late PNA more frequently resulted in high urinary PG fraction. Significance was more pronounced with PNA 10 days as cut-off point for early neonatal life compared to 7 days. Age 10 days is pivotal in early life propofol metabolism. This confirms earlier documented propofol clearance studies. This is the first report of the modified quantification assay used to determine urinary propofol metabolites in neonates.

Pharmacokinetics of paracetamol and its metabolites in women at delivery and post-partum.

AIM: A recent report on intravenous (i.v.) paracetamol pharmacokinetics (PK) showed a higher total clearance in women at delivery compared with non-pregnant women. To describe the paracetamol metabolic and elimination routes involved in this increase in clearance, we performed a population PK analysis in women at delivery and post-partum in which the different pathways were considered. METHODS: Population PK parameters using non-linear mixed effect modelling were estimated in a two-period PK study in women to whom i.v. paracetamol (2 g loading dose followed by 1 g every 6 h up to 24 h) was administered immediately following Caesarean delivery and in a subgroup of the same women to whom single 2 g i.v.loading dose was administered 10-15 weeks post-partum. RESULTS: Population PK analysis was performed based on 255 plasma and 71 urine samples collected in 39 women at delivery and in eight of these 39 women 12 weeks post-partum. Total clearance was higher in women at delivery compared with 12th post-partum week (21.1 vs. 11.7 l h⁻¹) due to higher clearances to paracetamol glucuronide (11.6 vs. 4.76 l h⁻¹), to oxidative metabolites (4.95 vs. 2.77 l h⁻¹) and of unchanged paracetamol (1.15 vs. 0.75 l h⁻¹). In contrast, there was no difference in clearance to paracetamol sulphate. CONCLUSION: The increased total paracetamol clearance at delivery is caused by a disproportional increase in glucuronidation clearance and a proportional increase in clearance of unchanged paracetamol and in oxidation clearance, of which the latter may potentially limit further dose increase in this patient group.

The impact of pregnancy on urinary ketorolac metabolites after single intravenous bolus.

Compared to female volunteers or postpartum, ketorolac clearance is higher at delivery. To explore the alterations that explain this higher clearance, urinary ketorolac metabolites collected at delivery (n = 40) were compared to female volunteers (unpaired, n = 8) or postpartum (paired, n = 8) following intravenous administration of 30 mg ketorolac tromethamine. A mean 38 (SD 9) % of the ketorolac dose was retrieved in 8-h urine collections. This was based on mean portions of 56 (20), 10 (14) and 33 (12) % for free ketorolac, ketorolac-glucuronide and p-hydroxy-ketorolac, respectively. The mean ketorolac-glucuronide portion at delivery (5 %) was lower compared to female volunteers (21 %) or postpartum (21 %) (p = 0.003 and p = 0.002, respectively). Similarly, there was a difference in mean portion of free urinary ketorolac at delivery when compared to healthy female volunteers (60-45 %, p = 0.046). Using paired statistics, the mean portion of total urinary ketorolac was lower (62-73 %, p = 0.015) while the portion retrieved as p-hydroxy-ketorolac was significantly higher at delivery compared to postpartum (38-28 %, p = 0.031). The differences in urine metabolites suggest that the increased ketorolac clearance at delivery is in part explained by increased metabolic clearance to p-hydroxy-ketorolac, reflecting increased oxidation activity.

The pharmacokinetics of a high intravenous dose of paracetamol after caesarean delivery: the effect of gestational age.

CONTEXT: Pregnancy affects intravenous paracetamol pharmacokinetics, but there are no studies on covariates of intravenous paracetamol pharmacokinetics around delivery. OBJECTIVES: To document the impact of gestational age at delivery on pharmacokinetics of a high intravenous dose of paracetamol. DESIGN: Pharmacokinetic study in women shortly after caesarean delivery. This study is an alternative analysis of a previously published study, using the same cohort but with added participants. SETTING: Single, tertiary perinatal care centre. PATIENTS: Of 36 patients recruited, pharmacokinetics analysis was performed in 34. Shortly following caesarean delivery, women received a loading dose (2 g) of intravenous paracetamol and four (at 1, 2, 4 and 6 h) plasma samples were collected. Of these 36 women, 28 had already been reported, but without further discrimination between preterm and term delivery, or any other covariate. Individual pharmacokinetic profiles were calculated assuming a linear one-compartment model with instantaneous input, first-order output. Covariates of between individual variability (preterm vs. term, maternal disease vs. healthy, twin vs. singleton pregnancy) of individual pharmacokinetics within this cohort were explored (Mann-Whitney U-test). MAIN OUTCOME MEASURES: Individual paracetamol pharmacokinetics. RESULTS: Mean (SD) paracetamol clearance was 22.4 l h(-1) (9.3) or - when corrected for body surface area - 11.5 l h(-1) m(-2) (4.0). No significant effects of twin pregnancy (n = 8) or maternal co-morbidity (n = 3) were observed, but mean clearance after preterm delivery (n = 12, <37 weeks gestational age) was significantly higher [13.8 (5.7) vs. 10.2 l h(-1) m(-2) (1.9), P = 0.028] compared with term delivery (n = 22). Similarly, there was a difference in mean distribution volume [0.83 (0.25) vs. 0.69 l kg(-1) (0.1), P = 0.037], resulting in the absence of differences in median elimination half-life [112 (28) vs. 119 min (19)]. CONCLUSION: Women who underwent a preterm caesarean delivery had a higher paracetamol clearance compared with term delivery. These pharmacokinetic differences illustrate the relevance of performing pharmacokinetic studies at delivery. We encourage clinicians to perform similar studies for other drugs administered in this group. TRIAL REGISTRATION: EudraCT 2010-020164-37.

The impact of Caesarean delivery on paracetamol and ketorolac pharmacokinetics: a paired analysis.

Pharmacokinetics is a first, but essential step to improve population-tailored postoperative analgesia, also after Caesarean delivery. We therefore aimed to quantify the impact of caesarean delivery on the pharmacokinetics of intravenous (iv) paracetamol (2 g, single dose) and iv ketorolac tromethamine (30 mg, single dose) in 2 cohorts eachof 8 women at caesarean delivery and to compare these findings with postpartum to quantify intrapatient changes. We documented a higher median paracetamol clearance at delivery when compared to 10-15 weeks postpartum (11.7 to 6.4 L/h·m², P < 0.01), even after correction for weight-related changes. Similar conclusions were drawn for ketorolac: median clearance was higher at delivery with a subsequent decrease (2.03 to 1.43 L/h·m², P < 0.05) in postpartum (17-23 weeks). These differences likely reflect pregnancy- and caesarean-delivery-related changes in drug disposition. Moreover, postpartum paracetamol clearance was significantly lower when compared to estimates published in healthy young volunteers (6.4 versus 9.6 L/h·m²), while this was not the case for ketorolac (1.43 versus 1.48 L/h·m²). This suggests that postpartum is another specific status in young women that merits focused, compound-specific pharmacokinetic evaluation.

Does intravenous paracetamol administration affect body temperature in neonates?

INTRODUCTION: Intravenous paracetamol (acetaminophen) has recently been registered for treatment of pain in neonates but the pharmacodynamics, including effects on body temperature, have not been reported. METHODS: A pooled analysis on body temperature recordings in neonates exposed to intravenous paracetamol was performed. Body temperature was recorded by skin probe and registered before and every 2 h following initiation of single or repeated intravenous paracetamol administration (up to 48 h). Repeated measures ANOVA and paired analysis were used to quantify differences following paracetamol exposure. RESULTS: The pooled analysis was based on 99 neonates (median weight 2.7 (range 0.5-5.4) kg, median postmenstrual age 37 (range 27-50) weeks). Based on observations in 93 normothermic (<37.8°C) neonates and six neonates with fever, it was documented that paracetamol administration does not affect body temperature in normothermic patients. In neonates with fever, the median decrease (-0.8°C) is most prominent in the first 2 h (p<0.01) following paracetamol administration with subsequent further normalisation. CONCLUSIONS: Administration of intravenous paracetamol does not result in hypothermia in normothermic neonates. In those with fever, maximal temperature reduction is achieved within 2 h following paracetamol administration.

Substantial variation in transplacental transfer of chemotherapeutic agents in a mouse model.

OBJECTIVE: Data on the transplacental transfer of chemotherapeutic agents are lacking. We aimed to measure the maternofetal transfer of cytotoxic drugs in a mouse model. STUDY DESIGN: The transplacental transfer of doxorubicin (9 mg/kg), epirubicin (11 mg/kg), vinblastine (6 mg/kg), carboplatin (50 mg/kg), paclitaxel (10 mg/kg), and cytarabine (100 mg/kg) was tested in a C57/Bl6J mouse model. Ninety minutes after intravenous (IV) drug injection on gestational day 18.5, maternal and fetal blood were collected simultaneously. Plasma drug levels were determined using high performance liquid chromatography or atomic absorption spectrometry. RESULTS: Fetal plasma concentrations of doxorubicin, epirubicin, vinblastine, and cytarabine were 5.1% ± 0.6% (n = 8), 4.8% ± 3.8% (n = 8), 13.8% ± 5.8% (n = 6), and 56.7% ± 22.6% (n = 6) of the maternal concentrations, respectively. Total platinum passed the mouse placenta easily (117.0% ± 38.9%, n = 6). Paclitaxel could not be detected in fetal plasma samples (n = 6). CONCLUSIONS: Substantial variations in transplacental transfer were noted among the tested drugs. Current findings contribute to the understanding of reported pregnancy outcomes in humans.

Prospective assessment of short-term propylene glycol tolerance in neonates.

INTRODUCTION: Propylene glycol (PG) is an unintentional frequently administered solvent in neonates despite the fact that PG accumulation potentially results in hyperosmolarity, lactic acidosis and renal/hepatic toxicity. METHODS: Prospective evaluation of renal (diuresis, creatinaemia, sodium), metabolic (base excess, anion gap, lactate, bicarbonate) and hepatic (alanine transaminase, aspartate aminotransferase, direct bilirubinaemia) tolerance to PG in (pre)term neonates following intravenous administration of formulations (paracetamol, phenobarbital, digoxin) that contain PG. Observations from 48 h before up to 48 after the last PG administration were described and compared (paired analysis). Clinical characteristics and observations collected following intravenous PG-paracetamol administration were compared with a historical cohort of neonates in whom similar (renal, hepatic) observations during exposure to a mannitol-containing paracetamol formulation were collected. RESULTS: 5566 observations were collected in 69 neonates before, during and following median PG exposure of 34 mg/kg/24 h (range 14-252). Progressive postnatal adaptation in renal, metabolic and hepatic function was documented, unrelated to the PG exposure. In the subgroup of 40 cases treated with intravenous PG-paracetamol, observations on renal and hepatic function were similar to a historical cohort of published observations following exposure to intravenous mannitol-paracetamol. CONCLUSIONS: Unintended PG administration (34 mg/kg/24 h) for a maximum of 48 h seems to be tolerated in (pre)term neonates and does not affect short-term postnatal adaptations. Further studies on PG disposition and the level of safe exposure to PG, including long-term safety data in neonates are needed.

No arguments for increased endothelial nitric oxide synthase activity in migraine based on peripheral biomarkers.

OBJECTIVES: To assess whether migraine patients display a chronic nitric oxide synthase (NOS) hyperactivity by comparing the nitric oxide (NO) production before and following a loading dose of L-arginine between migraine patients (interictally) and matched healthy control subjects. In addition, we evaluated whether a loading dose of L-arginine triggers an acute migraine headache in migraineurs. SUBJECTS AND METHODS: Twenty healthy subjects and 20 migraine patients participated in a 2-period, randomised, double-blind, placebo-controlled study. Each subject received a 30-min infusion, by peripheral vein, of 30 g L-arginine hydrochloride or placebo (i.e. an equal volume of 0.9% saline solution). Meanwhile, biomarkers associated with the L-arginine-NO pathway (i.e. exhaled NO/nasal NO), plasma citrulline and urinary excretion of nitrite/nitrate and cGMP were assessed before and for 6 h following the start of the infusion. RESULTS: At baseline, exhaled NO and nasal NO were higher in migraineurs compared to healthy subjects (mean±95% confidence interval): 15.9 (8.8, 23.0) parts per billion (ppb) versus 10.8 (7.0, 14.5) ppb for exhaled NO (P=0.04) and 76.3 (61.2, 91.4) versus 61.6 (51.2, 72.0) ppb for nasal NO (P=0.03), respectively. The AUC0-6 in ppb for exhaled NO and nasal NO following L-arginine or saline infusion did not differ between both groups. The increase in L-citrulline, following L-arginine infusion, was smaller in migraine patients (15 (13, 18) µmol/l) compared to healthy volunteers (19 (16, 23) µmol/l; P=0.046). In healthy subjects, both nitrate and cGMP excretion were higher following L-arginine compared to placebo infusion: 132.63 (100.24, 165.02) versus 92.07 (66.33, 117.82) µmol/mmol creatinine for nitrate (P=0.014) and 50.53 (42.19, 58.87) versus 39.64 (33.94, 45.34) nmol/mmol creatinine for cGMP (P=0.0003), respectively. In migraineurs, excretion of these biomarkers was comparable following L-arginine or saline infusion. CONCLUSIONS: The results of the present study do not support the idea of a generalised increase in NO synthase activity in migraine patients outside of a migraine attack. The smaller increase in plasma L-citrulline, urinary nitrate and cGMP excretion following L-arginine infusion in migraine patients might indicate dysfunction of endothelial NO synthase.

Pharmacokinetics of chemotherapeutic agents in pregnancy: a preclinical and clinical study.

OBJECTIVE: To determine the impact of physiologic changes of pregnancy on pharmacokinetics of chemotherapeutic agents. DESIGN: A preclinical and a clinical case-control trial. SETTING: Institute of Primate Research Nairobi and collaborating hospitals in Belgium, the Netherlands and Czech Republic. POPULATION: Pregnant and nonpregnant women and baboons receiving chemotherapy. METHODS: Chemotherapy pharmacokinetics was compared between the pregnant and nonpregnant state. Standard-dosed chemotherapy regimens were administered in pregnant and nonpregnant baboons/women, followed by serial blood samplings. Drug plasma levels were determined using high performance liquid chromatography and atomic absorption spectrometry. MAIN OUTCOME MEASURES: Area under the curve (AUC), maximal plasma concentration, terminal elimination half-life, clearance and distribution volume of each drug in pregnant and nonpregnant state. RESULTS: Intraindividual comparative pharmacokinetic data were obtained for doxorubicin and paclitaxel/platinum in three and two baboons, respectively. In the clinical trial, two patients were exposed to doxorubicin and one patient was exposed to paclitaxel/platinum during and after pregnancy. Furthermore, a pooled analysis was performed based on 16 cycles of pregnant and 11 cycles of nonpregnant women. Numbers of pregnant/nonpregnant patients were 5/2, 7/5, 4/4 and 2/2 for paclitaxel, doxorubicin, epirubicin and platinum, respectively. For all drugs tested in the preclinical and clinical study, a decreased AUC and maximal plasma concentration and an increased distribution volume and clearance were observed in pregnancy. CONCLUSIONS: Although numbers were too small for statistical significance, pregnancy-associated physiologic alterations appear to lead to a decrease in plasma exposure of chemotherapeutic drugs. The importance of long-term follow-up of women treated with chemotherapy during pregnancy is underscored.

Transplacental transfer of paclitaxel, docetaxel, carboplatin, and trastuzumab in a baboon model.

BACKGROUND: The paucity of data on fetal effects of prenatal exposure to chemotherapy prompted us to study the transplacental transport of commonly used anticancer agents in a pregnant baboon model. METHODS: Single or combination chemotherapy with paclitaxel, docetaxel, carboplatin, and trastuzumab was administered to 9 baboons at a mean (SD) gestational age of 117 (26) days (paclitaxel, 100 mg/m2 [n = 2]; docetaxel, 100 mg/m2 [n = 2]; paclitaxel, 175 mg/m2 with carboplatin, area under the curve of 6 at standard dosage [n = 2] and 50% dosage [n = 1]; docetaxel, 75 mg/m2 with carboplatin, area under the curve 6 [n = 1]; and docetaxel, 75 mg/m2 with trastuzumab, 8 mg/kg [n = 1]). Serial fetal and maternal blood samples, amniotic fluid, maternal urine, and fetal and maternal tissue samples were collected for the first 76 hours after drug infusion. Levels of carboplatin were determined by atomic absorption spectrometry, docetaxel and paclitaxel by high-performance liquid chromatography, and trastuzumab by enzyme-linked immunosorbent assay. RESULTS: Fetal plasma concentrations of carboplatin averaged 57.5% (14.2%) of maternal concentrations (n = 7). Fetal plasma concentrations were 1.5% (0.8%) of maternal concentrations (n = 7). Immediately after ending the infusion, paclitaxel was not detectable in fetal tissues, whereas, after 3 hours, fetal tissues contained 15% of maternal tissue concentrations.Docetaxel could not be detected in fetal blood samples (n = 9). In the first 3 hours after docetaxel infusion, fetal tissues contained 5.0% to 50.0% of maternal tissue concentrations, whereas equal fetal and maternal tissue concentrations were found after 26 and 76 hours.The transplacental passages of trastuzumab were 85.0% and 3.0%, 2 and 26 hours after trastuzumab infusion, respectively. After 26 hours, amniotic fluid contained 36.4% of the fetal plasma concentration. Fetal tissue concentrations varied between 5.0% and 14.0% of the maternal concentration. CONCLUSION: Variable plasma and/or tissue concentrations of taxanes, carboplatin, and trastuzumab were encountered in the fetal compartment. These data are important when cancer treatment is considered during pregnancy and underline the need for long-term follow-up of children after prenatal exposure to these cytotoxic agents.

In vivo glucuronidation activity of drugs in neonates: extensive interindividual variability despite their young age.

Compared with phase I isoenzymes, data on isoenzyme-specific phenotypic activity of uridine diphosphate glucuronosyltransferase (UGT) and its covariates in neonates are limited. In vivo observations on morphine, paracetamol (acetaminophen), and propofol disposition throughout childhood confirm the overall low-glucuronidation activity in neonates observed in in vitro studies. In addition to the phenotypic low-glucuronidation activity, in vivo observations of bilirubin (UGT1A1), morphine (UGT2B7), paracetamol (UGT1A6), and propofol (UGT1A9) glucuronidation in neonates display extensive interindividual variability, only in part explained by postmenstrual and postnatal age. Covariates like disease state characteristics (decreased morphine metabolism during therapeutic head cooling), genetic polymorphisms (UGT1A1 genetic variants and differences in bilirubin metabolism), or environmental factors (increased urinary excretion of paracetamol-glucuronide by repeated administration of paracetamol) further contribute to this variability. A focused approach to unveil covariates of the interindividual range is needed to improve our knowledge on drug disposition in early life.

Vinblastine and doxorubicin administration to pregnant mice affects brain development and behaviour in the offspring.

BACKGROUND: Administration of chemotherapy during the fetal phase of pregnancy may put late-developing organs like the central nervous system at risk. METHODS: Transplacental transfer of doxorubicin and vinblastine was measured in C57/BJ mice by high-performance liquid chromatographic detection of the drugs in maternal and fetal plasma, 90 min after intravenous injection. Further, doxorubicin, vinblastine or saline were administered to pregnant C57/6J mouse dams on gestational day 17.5. Effects on brain morphology of the offspring were examined at 24h p.i. (immediate phase) and at 4-5 months p.i. (residual phase), using light- and electron microscopy. At the age of 3 months, offspring performed a behavioural test battery addressing neuromotor performance, exploration and anxiety, and learning and memory. RESULTS: Fetal plasma levels of doxorubicin and vinblastine reached respectively 5.0+/-0.2% and 13.9+/-2.4% of the maternal plasma levels. In the immediate phase, pathological examination revealed endothelial and perivascular parenchymal damage to the neocortical subventricular zone and a less constant thickening of the leptomeninx, in some cases also cortical lamination defects were noted. Brain histology was within normal limits in the mice of the residual phase group. Behavioural testing revealed subtle differences between drug-exposed and control mice. Grip strength was reduced in drug-exposed mice, but other tests for motor performance were normal. Several exploratory measures were altered, and there were some indications of increased anxiety in the drug-exposed mice. In the passive avoidance task, step-through latency was shorter in the drug-exposed mice, but their normal performance in the Morris water maze indicated that this was probably not due to impaired memory. CONCLUSION: The current preclinical data reveal subtle changes in behaviour and transiently also in brain morphology in the mice that were prenatally exposed to vinblastine or doxorubicin.

Cefazolin plasma protein binding saturability during pregnancy.

This article aims to document cefazolin (CFZ) plasma binding and its covariates during pregnancy and compare these observations with previously reported observations in nonpregnant adults. Maternal CFZ plasma samples were collected during in utero surgery. The unbound CFZ fraction was reported by median and range. Correlation (Spearman) and multiple regression were used to identify covariates (total CFZ concentration, albuminemia, gestational age) of the unbound CFZ fraction. Observations during pregnancy were compared with observations in nonpregnant adults (unpaired t test, multiple regression). Plasma (N = 130) samples were collected during 30 interventions. The median unbound CFZ fraction was 0.25 (range 0.14-0.41). Correlations between the unbound CFZ fraction and total CFZ plasma concentration (0.46), time after administration (-0.38), albuminemia (-0.39) and gestational age (-0.19) were statistically significant. The median unbound CFZ fraction was higher during pregnancy when compared to observations in nonpregnant adults (0.25 vs. 0.19, P < 0.001). In a multiple-regression model, total plasma CFZ concentration and albuminemia were covariates of the unbound CFZ fraction (r(2) = 0.4). The concept of saturability of CFZ plasma protein binding has been confirmed during pregnancy, but the free CFZ fraction is higher, likely explained by the lower albuminemia during pregnancy.

Use of propafenone for conversion of chronic atrial fibrillation in horses.

OBJECTIVE: To investigate effects of IV administration of propafenone for naturally occurring and experimentally induced chronic atrial fibrillation in horses. ANIMALS: 2 horses with naturally occurring atrial fibrillation and 4 horses with pacing-induced atrial fibrillation. PROCEDURES: Horses received a bolus of propafenone (2 mg/kg, IV over 15 minutes). If atrial fibrillation persisted after 20 minutes, a continuous infusion of propafenone (7 microg/kg/min) was given for 120 minutes. Before, during, and after treatment, plasma propafenone concentrations, hematologic and serum biochemical values, and electolyte concentrations analyses were determined and clinical signs were monitored. Surface ECGs were recorded. If propafenone treatment failed, quinidine sulfate was administered. RESULTS: Bolus and continuous infusion induced minimal adverse effects. During the 15-minute bolus administration, a slight increase in heart rate was observed and horses appeared more sensitive to external stimuli. Throughout treatment, no significant changes were observed in respiratory rate, QRS or corrected QT duration, or results of hematologic analyses. Although a significant increase in F-wave interval and atrial fibrillation cycle length was observed and plasma propafenone concentrations (569 to 1,268 ng/mL) reached the human therapeutic range (64 to 1,044 ng/mL), none of the horses cardioverted to sinus rhythm. Sinus rhythm could be restored in all horses via standard oral administration of quinidine. CONCLUSIONS AND CLINICAL RELEVANCE: A slow IV bolus of 2 mg of propafenone/kg followed by a continuous infusion of 7 microg/kg/min over 2 hours was not an effective treatment for chronic atrial fibrillation in horses.

Pharmacokinetics of caspofungin and voriconazole in critically ill patients during extracorporeal membrane oxygenation.

OBJECTIVES: During extracorporeal membrane oxygenation (ECMO), drug disposition changes significantly. Plasma concentrations are altered due to an expanded circulating volume leading to a decreased elimination. In addition, adsorption and sequestration of drugs by the ECMO circuit components may further alter pharmacokinetics. Treating patients during the ECMO period with antifungals is difficult. Loss in the ECMO circuit can potentially result in sub-therapeutic levels. METHODS: Two cases are presented in which caspofungin and voriconazole levels and pharmacokinetic parameters were determined during the ECMO period. RESULTS: Mean caspofungin trough and peak levels were 3.73 and 11.95 microg/mL. These are comparable to previously reported ones. Also pharmacokinetic parameters were identical to those reported in the literature. It seems that caspofungin is not sequestrated by the ECMO circuit, which is expected based on its low log P value. During the first days of ECMO therapy, voriconazole trough and peak levels did not differ much from those determined prior to ECMO therapy. However, at the start of ECMO therapy, the voriconazole dose was increased from 280 to 400 mg twice daily as loss due to binding to the circuit was expected. This increase was not immediately reflected in higher voriconazole levels, which may be due to drug sequestration by the circuit. However, the voriconazole half-life was extended up to 20 h in our patient. Two days after the dose increase, levels reached troughs >10 microg/mL and peaks of around 15 microg/mL, exceeding the therapeutic interval for voriconazole. This can possibly be explained by the saturation of binding sites on the ECMO circuit. CONCLUSIONS: Our results suggest that adequate caspofungin plasma levels are maintained during ECMO. In the case of voriconazole, it is recommended to monitor plasma levels to ensure efficacy and avoid toxicity.

Cefazolin pharmacokinetics in maternal plasma and amniotic fluid during pregnancy.

OBJECTIVE: To study cefazolin pharmacokinetics in maternal plasma and amniotic fluid during pregnancy. STUDY DESIGN: Newly collected time-concentrations profiles and reported studies investigating cefazolin disposition (plasma, amniotic fluid) were pooled. Nonlinear mixed effect modeling was applied. A 2-compartment linear disposition model was used to fit cefazolin plasma observations. A third compartment was used to model amniotic fluid concentration. RESULTS: One hundred eighty-seven plasma and 96 amniotic fluid samples were collected in 82 pregnancies (17-40 weeks gestational age). Cefazolin clearance and distribution estimates were 7.44 L/h and 12.04 L without gestational age-dependent trends in maternal plasma. The equilibration half-life (T(eq)) between plasma and amniotic fluid at term gestational age was 4.4 hours, increased with decreasing gestational age, and was 9.09 times longer in patients with polyhydramnios. CONCLUSION: Cefazolin clearance and distribution volume are increased during pregnancy. The cefazolin T(eq) depends on gestational age and polyhydramnios. On the basis of these observations, dosing regimes to attain higher amniotic fluid concentrations were formulated.