Manometric evaluation of the motilin receptor agonist camicinal (GSK962040) in humans.

BACKGROUND: The gut hormone motilin stimulates gastrointestinal motility by inducing gastric phase III of the migrating motor complex (MMC) and enhancing the rate of gastric emptying. Camicinal (GSK962040), a small molecule motilin receptor agonist, has been shown to increase gastrointestinal motility. METHODS: In this proof of concept study the effects of camicinal on MMC activity, esophageal and gastric pH was evaluated in eight healthy volunteers as a secondary endpoint. Doses of 50 and 150 mg were compared to placebo for a period of 24 hours in a double-blinded randomized crossover trial. KEY RESULTS: The 50 mg dose (n=4) of camicinal had no significant impact on gastroduodenal manometry or pH parameters. A single dose of 150 mg (n=4) induced a gastric phase III after 0:34 h (0:25-0:58), which was significantly faster compared to placebo (18:15 h (4:32-22:16); P=.03). Moreover, the high dose significantly increased the occurrence of gastric phase III contractions compared to placebo (12% vs 39%; P=.0003). This increase in gastric phase III contractions during a period of 24 hour was due to an increased occurrence of gastric phases III during the daytime (5% vs 50%; P=.0001). The same dose however did not affect small bowel manometry parameters or esophageal and gastric pH. CONCLUSIONS AND INFERENCES: Considering its stimulating effect on the MMC and gastric emptying, camicinal is an attractive candidate for the treatment of gastroparesis and gastroesophageal reflux disease. This trial was registered at clinicaltrials.gov as NCT00562848.

Safety profile of the 9-valent human papillomavirus vaccine: assessment in prior quadrivalent HPV vaccine recipients and in men 16 to 26 years of age.

A 9-valent HPV (9vHPV) vaccine has been developed to protect against HPV type 6/11/16/18/31/33/45/52/58-related infection and disease. Previous safety analyses from 7 clinical trials conducted in 9vHPV vaccine recipients 9-26 years of age, including comparisons of 9vHPV and quadrivalent HPV (qHPV) vaccines in girls and women 16-26 years of age, showed that the 9vHPV vaccine was generally well tolerated. Additional safety analyses were conducted to include the results of new clinical studies. The safety profile of the 9vHPV vaccine in prior qHPV vaccine recipients (n = 3756 from 1 randomized controlled trial and 2 open-label extension studies) and young men (n = 248 9vHPV and n = 248 qHPV vaccine recipients from 1 randomized controlled trial) was evaluated. Vaccine was administered as a 3-dose regimen (at Day 1 and Months 2 and 6), and adverse events (AEs) were monitored. The most common AEs were injection-site events (91.1% and 79.0% in prior qHPV vaccine recipients and young men, respectively), the majority of which were mild. Discontinuations due to an AE were rare (0.2% and 0.0% among prior qHPV vaccine recipients and young men, respectively). In young men, the AE profile of the 9vHPV vaccine was generally similar to that of the qHPV vaccine. Overall, the 9vHPV vaccine was generally well tolerated in prior qHPV vaccine recipients and in young men, with an AE profile generally consistent with that previously reported with the broader clinical program.

Single-Dose and Multiple-Dose Pharmacokinetics of Vaniprevir in Healthy Men.

Vaniprevir is an inhibitor of the hepatitis C virus (HCV) NS3/4A protease. The aim of these double-blind, placebo-controlled phase I studies was to evaluate the safety and pharmacokinetics of vaniprevir in healthy male volunteers. The primary objective for both studies was the safety and tolerability of vaniprevir. Single-dose and steady-state pharmacokinetics were also assessed. In both studies, there was no apparent relationship between the frequency or intensity of adverse events and vaniprevir dose. At single doses >20 mg, the plasma area under the curve (AUC)0-∞ and maximum concentration (Cmax ) increased in a greater-than-dose-proportional manner. The geometric mean ratios (GMRs; fed/fasted) were 1.22 and 0.79 for AUC0-∞ and Cmax , respectively. Following multiple doses, GMR accumulations for AUC0-12h and Cmax (day 14/day 1) ranged from 1.53 to 1.90 and from 1.41 to 1.92, respectively. These data support the use of vaniprevir with peginterferon and ribavirin in patients with HCV infection.

TRPV1 dysfunction in cystinosis patients harboring the homozygous 57 kb deletion.

Cystinosis is a rare autosomal recessive disorder characterized by lysosomal cystine accumulation due to loss of function of the lysosomal cystine transporter (CTNS). The most common mutation in cystinosis patients of Northern Europe consists of a 57-kb deletion. This deletion not only inactivates the CTNS gene but also extends into the non-coding region upstream of the start codon of the TRPV1 gene, encoding the capsaicin- and heat-sensitive ion channel TRPV1. To evaluate the consequences of the 57-kb deletion on functional TRPV1 expression, we compared thermal, mechanical and chemical sensitivity of cystinosis patients with matched healthy controls. Whereas patients heterozygous for the 57-kb deletion showed normal sensory responses, homozygous subjects exhibited a 60% reduction in vasodilation and pain evoked by capsaicin, as well as an increase in heat detection threshold. Responses to cold, mechanical stimuli or cinnamaldehyde, an agonist of the related nociceptor channel TRPA1, were unaltered. We conclude that cystinosis patients homozygous for the 57-kb deletion exhibit a strong reduction of TRPV1 function, leading to sensory deficiencies akin to the phenotype of TRPV1-deficient mice. These deficits may account for the reported sensory alterations and thermoregulatory deficits in these patients, and provide a paradigm for life-long TRPV1 deficiency in humans.

Pharmacokinetics and Pharmacodynamics of Omarigliptin, a Once-Weekly Dipeptidyl Peptidase-4 (DPP-4) Inhibitor, After Single and Multiple Doses in Healthy Subjects.

The pharmacokinetics (PK) and pharmacodynamics (PD) of omarigliptin, a novel once-weekly DPP-4 inhibitor, were assessed following single and multiple doses in healthy subjects. Absorption was rapid, and food did not influence single-dose PK. Accumulation was minimal, and steady state was reached after 2 to 3 weeks. Weekly (area under the curve) AUC and Cmax displayed dose proportionality within the dose range studied at steady state. The average renal clearance of omarigliptin was ∼2 L/h. DPP-4 inhibition ranged from ∼77% to 89% at 168 hours following the last of 3 once-weekly doses over the dose range studied. Omarigliptin resulted in ∼2-fold increases in weighted average postprandial active GLP-1. Omarigliptin acts by stabilizing active GLP-1, which is consistent with its mechanism of action as a DPP-4 inhibitor. Administration of omarigliptin was generally well tolerated in healthy subjects, and both the PK and PD profiles support once-weekly dosing. A model-based assessment of QTc interval risk from the single ascending dose study predicted a low risk of QTc prolongation within the likely clinical dose range, a finding later confirmed in a thorough QT trial.

Estradiol and weight are covariates of paracetamol clearance in young women.

AIM: Paracetamol clearance differs between pregnant and non-pregnant women and between women with or without specific oral contraceptives (OCs). However, an association between female sex hormones and paracetamol clearance has never been explored. METHODS: In total, 49 women at delivery, 8 female control subjects without OC use, historical data of 14 women taking OCs, and 15 postpartum observations with and without OCs were pooled to explore covariates of paracetamol clearance. All received a single intravenous 2-gram paracetamol dose, and blood samples were collected up to 6 h after dosing. High-performance liquid chromatography was used to quantify paracetamol. The area under the curve to time infinity (AUC0-∞) was determined and clearance (l/h·m(2)) was calculated by dose/ AUC0-∞. In addition, estradiol and progesterone were quantified by ELISA with electro-chemiluminescence. RESULTS: Median paracetamol clearance at delivery was significantly higher when compared to postpartum or non-pregnant women (11.9 vs. 6.42 and 8.4 l/h·m(2), at least p < 0.05), while an association between paracetamol clearance and estradiol was observed (R = 0.494, p < 0.0001). In non-pregnant subjects, there was no impact of OC exposure on paracetamol clearance. Multiple regression revealed a linear association (Radj = 0.41, p < 0.001) between paracetamol clearance and weight (p = 0.0462) and estradiol (p < 0.0001). CONCLUSION: Estradiol and weight in part explain the variation in paracetamol clearance in young women.

Weight, pregnancy and oral contraceptives affect intravenous paracetamol clearance in young women.

OBJECTIVES: Because of the extensive variability in paracetamol clearance in young women, published data were pooled with newly collected observations in search of covariates of paracetamol pharmacokinetics (PK) within this specific population. SUBJECTS AND METHODS: PK estimates and clinical characteristics [pregnant, weight, exposure to oral contraceptives (OC)] in young women following IV loading dose (2 g paracetamol) were pooled, using a non-compartmental linear disposition model in individual time-concentration profiles. Data were reported by median and range. Rank correlation was used to link clearance (l/h) to weight, Mann Whitney U test to compare clearance (l/h.m-2) between subgroups (pregnant, OC exposure). Finally, a multiple regression model with clearance (l/h) in all women and all non-pregnant women was performed. RESULTS: Based on 73 paracetamol PK estimates, a 8-fold variability in clearance (range 7.1-62.2 l/h) was documented, in part explained by a correlation (r2=0.36) between clearance (l/h) and weight. Clearance (l/h and l/h.m-2) and distribution volume (l) at delivery (n=36) were higher compared to non-pregnant observations. In non-pregnant women, women on OC (n=20) had a higher paracetamol clearance (l/h.m-2) compared to women (n=17) not on OC (p = 0.023). Weight (p = 0.0043) and pregnancy (p = 0.02) were independent variables (r=0.56) of paracetamol clearance (l/h). In non-pregnant women, weight (p = 0.009) and OC exposure (p = 0.03) were independent variables (r=0.51). CONCLUSIONS: Weight, pregnancy and OC result in higher clearance of IV paracetamol in young women. Besides compound specific relevance, these findings also unveil covariates of drug metabolism in young women.

Population pharmacokinetic modelling of total and unbound cefazolin plasma concentrations as a guide for dosing in preterm and term neonates.

OBJECTIVES: Cefazolin is frequently administered for antimicrobial prophylaxis and treatment of infections. In neonates, pharmacokinetic observations are limited and dosing regimens variable. The aim of this study was to describe the pharmacokinetics of cefazolin in neonates based on total and unbound concentrations to optimize cefazolin dosing. METHODS: Thirty-six neonates [median birth body weight 2720 (range 540-4200) g, current body weight (cBW) 2755 (830-4200) g and postnatal age (PNA) 9 (1-30) days] receiving intravenous cefazolin (50 mg/kg/8 h) were included. Based on 119 total and unbound plasma concentrations, a population pharmacokinetic analysis with a covariate analysis was performed. Monte Carlo simulations were performed aiming for unbound concentrations above an MIC of 8 mg/L (>60% of the time) in all patients. RESULTS: A one-compartment pharmacokinetic model was developed in which total and unbound concentrations were linked by maximum protein binding (Bmax) of 136 mg/L and a dissociation constant (KD) for cefazolin protein binding of 46.5 mg/L. cBW was identified as covariate for volume of distribution (V), bBW and PNA for clearance and albumin plasma concentration for Bmax, explaining 50%, 58% and 41% of inter-individual variability in V, clearance and Bmax, respectively. Based on Monte Carlo simulations, a body weight- and PNA-adapted dosing regimen that resulted in similar exposure across different weight and age groups was proposed. CONCLUSIONS: A neonatal pharmacokinetic model taking into account total and unbound cefazolin concentrations with saturable plasma protein binding was identified. As cBW and PNA were the most important covariates, these may be used for individualized dosing in neonates.

Development of an experimental model to study trigeminal nerve-mediated vasodilation on the human forehead.

BACKGROUND: During migraine, trigeminal sensory nerve terminals release calcitonin gene-related peptide (CGRP), inducing nociception and vasodilation. Applied on the skin, capsaicin activates the transient receptor potential vanilloid type 1 (TRPV1) channel and releases CGRP from sensory nerve terminals, thus increasing dermal blood flow (DBF). Using capsaicin application and electrical stimulation of the forehead skin, a trigeminal nerve-innervated dermatome, we aimed to develop a model to measure trigeminal nerve-mediated vasodilation in humans. METHODS: Using laser Doppler imaging, forehead DBF responses to application of capsaicin (0.06 mg/ml and 6.0 mg/ml) and saline, with and without iontophoresis, were studied in healthy subjects. The within-subject coefficient of variation (WCV) of repeated DBF measurements was calculated to assess reproducibility. RESULTS: Maximal DBF responses to 6.0 mg/ml capsaicin with and without iontophoresis did not differ (Emax 459 ± 32 and 424 ± 32 arbitrary units (a.u.), WCV 6 ± 4%). In contrast, DBF responses to 0.06 mg/ml capsaicin were significantly larger with than without iontophoresis (Emax 307 ± 60 versus 187 ± 21 a.u., WCV 21 ± 13%). Saline with iontophoresis significantly increased DBF (Emax: 245 ± 26 a.u, WCV 11 ± 8%), while saline application without iontophoresis did not affect DBF. CONCLUSION: Topical application of capsaicin and electrical stimulation induce reproducible forehead DBF increases and therefore are suitable to study trigeminal nerve-mediated vasodilation in humans.

Pharmacokinetics of intravenous ketorolac following caesarean delivery.

BACKGROUND: Drug disposition is altered by pregnancy and the peripartum period but data on intravenous ketorolac pharmacokinetics following caesarean delivery have not been previously reported. METHODS: At the end of caesarean delivery, women received an intravenous bolus of ketorolac tromethamine 30 mg (immediate postpartum, Group IP). Plasma samples were collected at 1, 2, 4, 6 and 8h. A similar pharmacokinetic study was repeated in a subgroup of these women 4-5 months after delivery (late postpartum, Group LP) and in a group of unrelated, healthy non-pregnant female volunteers (controls, Group C). A non-compartmental linear disposition model was applied to analyse individual ketorolac time-concentration profiles. Results at delivery were compared with controls using unpaired or paired statistics as appropriate. Covariates of pharmacokinetic estimates at delivery were examined. RESULTS: Thirty-nine women were studied at caesarean delivery, of whom eight were re-evaluated 4-5 months later. In addition, eight volunteers were studied. Clearance in Group IP was higher compared to Groups LP and C (2.11 vs. 1.43 and 1.07 L/h·m(2) respectively, P<0.05). Volume of distribution was also increased in Group IP compared to Groups LP and C (0.24 vs. 0.16 and 0.17 L/kg respectively, P<0.05). No significant covariates of pharmacokinetic estimates, including gestational age, preterm vs. term, twin vs. singleton and maternal co-morbidity, were seen in Group IP. CONCLUSIONS: Ketorolac clearance and distribution volume are significantly increased following caesarean delivery. These data provide pharmacokinetic estimates on which to base studies on post caesarean analgesia.

Cefazolin plasma protein binding and its covariates in neonates.

Cefazolin (CFZ) is highly and saturably bound to human serum albumin (HSA) in adults. We aim to describe CFZ protein binding and its covariates in neonates. In neonates to whom intravenous CFZ (50 mg/kg) was administered prior to a surgical procedure, total and unbound CFZ plasma concentrations (mg/l) were determined at 0.5, 2, 4 and 8 h after CFZ administration. Linear and multiple regression analyses were used to document covariates of unbound CFZ fraction. The Wilcoxon signed-rank test was used for the paired analysis of unbound CFZ fractions. In 40 patients with a median weight of 2,767 (range 830-4,200) g and a postmenstrual age (PMA) of 39 (25-45) weeks, 131 samples were collected. The median unbound CFZ fraction was 0.39 (0.10-0.73). Linear regression of unbound CFZ fraction versus unbound CFZ plasma concentration (R (2) = 0.39) had a slope significantly different from zero (p < 0.001). In a multiple regression analysis, albuminaemia, total CFZ concentration, indirect bilirubinaemia and PMA resulted in an R (2) value of 0.496. The median unbound CFZ fraction at the peak concentration (0.46, range 0.28-0.69) was significantly higher compared to the trough level (0.36, range 0.17-0.73) (p < 0.001). The between- and within-patient saturability of CFZ plasma protein binding were documented in neonates. The median unbound CFZ fraction in neonates is higher than in adults and depends partly on albuminaemia, total CFZ concentration, indirect bilirubinaemia and PMA. Integration of CFZ protein binding in future pharmacokinetic/pharmacodynamic research is warranted in order to optimise neonatal CFZ dosing. We recommend protein binding assessment in the neonatal pharmacokinetic evaluation of highly protein-bound or clinically relevant drugs.

Equivalent dynamic human brain NK1-receptor occupancy following single-dose i.v. fosaprepitant vs. oral aprepitant as assessed by PET imaging.

The type 1 neurokinin receptor (NK1R) antagonist aprepitant and its i.v. prodrug fosaprepitant have been approved for prevention of acute and delayed nausea and vomiting associated with chemotherapy. This study evaluated the magnitude and duration of brain NK1R occupancy over a period of 5 days after single-dose i.v. infusion of 150-mg fosaprepitant and single-dose oral administration of 165-mg aprepitant, using serial [(18)F]MK-0999 positron emission tomography (PET) in 16 healthy subjects. Each subject underwent three scans. Brain NK1R occupancy rates after i.v. fosaprepitant at time to peak concentration (T(max); ~30 min), 24, 48, and 120 h after the dose were 100, 100, ≥97, and 41-75%, respectively. After aprepitant, NK1R occupancy rates at these time points (T(max) ~4 h) were ≥99, ≥99, ≥97, and 37-76%, respectively. Aprepitant plasma concentration profiles were comparable for the two dosage forms. The study illustrates the utility of PET imaging in determining central bioequivalence in a limited number of subjects.

Pharmacokinetics of a loading dose of intravenous paracetamol post caesarean delivery.

BACKGROUND: The postpartum period affects drug disposition, but data of intravenous paracetamol loading dose pharmacokinetics immediately following caesarean delivery have not yet been reported. METHODS: Immediately following caesarean delivery, women received a 2-g loading dose of intravenous paracetamol. Plasma samples were collected at 1, 2, 4 and 6 h. Individual pharmacokinetics were calculated assuming a linear one-compartment model with instantaneous input and first-order output. Data were reported using median and range. RESULTS: Twenty-eight patients undergoing caesarean delivery were recruited (age 31.5 [20-42] years, weight 79 [57-110] kg, body surface area 1.9 [1.5-2.4]m(2)). Median paracetamol plasma concentrations after 1, 2, 4 and 6 h were 22.5, 15.25, 7.9, and 3.9 mg/L respectively. Paracetamol clearance was 20.3 (11.8-62.8) L/h or 10.9 (7-23.8)L/hm(2), distribution volume 58.3 (42.9-156) L or 0.72 (0.52-1.56) L/kg. CONCLUSION: Pharmacokinetics of intravenous paracetamol have been estimated following caesarean delivery. Although limited to a loading dose shortly after surgery, the results are clinically relevant since this is the first description in this patient population. These data provide evidence on which to base further integrated pharmacokinetic/pharmacodynamic studies in peripartum analgesia.

MRK-409 (MK-0343), a GABAA receptor subtype-selective partial agonist, is a non-sedating anxiolytic in preclinical species but causes sedation in humans.

MRK-409 binds to α1-, α2-, α3- and α5-containing human recombinant GABA(A) receptors with comparable high affinity (0.21-0.40 nM). However, MRK-409 has greater agonist efficacy at the α3 compared with α1 subtypes (respective efficacies relative to the full agonist chlordiazepoxide of 0.45 and 0.18). This compound readily penetrates the brain in rats and occupies the benzodiazepine site of GABA(A) receptors, measured using an in vivo [(3)H]flumazenil binding assay, with an Occ(50) of 2.2 mg/kg p.o. and a corresponding plasma EC(50) of 115 ng/mL. Behaviourally, the α3-preferring agonist efficacy profile of MRK-409 produced anxiolytic-like activity in rodent and primate unconditioned and conditioned models of anxiety with minimum effective doses corresponding to occupancies, depending on the particular model, ranging from ∼35% to 65% yet there were minimal overt signs of sedation at occupancies greater than 90%. In humans, however, safety and tolerability studies showed that there was pronounced sedation at a dose of 2 mg, resulting in a maximal tolerated dose of 1 mg. This 2 mg dose corresponded to a C(max) plasma concentration of 28 ng/mL, which, based on the rodent plasma EC(50) for occupancy of 115 ng/mL, suggested that sedation in humans occurs at low levels of occupancy. This was confirmed in human positron emission tomography studies, in which [(11)C]flumazenil uptake following a single dose of 1 mg MRK-409 was comparable to that of placebo, indicating that occupancy of GABA(A) receptor benzodiazepine binding sites by MRK-409 was below the limits of detection (i.e. <10%). Taken together, these data show that MRK-409 causes sedation in humans at a dose (2 mg) corresponding to levels of occupancy considerably less than those predicted from rodent models to be required for anxiolytic efficacy (∼35-65%). Thus, the preclinical non-sedating anxiolytic profile of MRK-409 did not translate into humans and further development of this compound was halted.

Preclinical and clinical pharmacology of TPA023B, a GABAA receptor α2/α3 subtype-selective partial agonist.

In the accompanying paper we describe how MRK-409 unexpectedly produced sedation in man at relatively low levels of GABA(A) receptor occupancy (∼10%). Since it was not clear whether this sedation was mediated via the α2/α3 or α1 GABA(A) subtype(s), we characterized the properties of TPA023B, a high-affinity imidazotriazine which, like MRK-409, has partial agonist efficacy at the α2 and α3 subtype but is an antagonist at the α1 subtype, at which MRK-409 has weak partial agonism. TPA023B gave dose- and time-dependent occupancy of rat brain GABA(A) receptors as measured using an in vivo [(3)H]flumazenil binding assay, with 50% occupancy corresponding to a respective dose and plasma drug concentration of 0.09 mg/kg and 19 ng/mL, the latter of which was similar to that observed in mice (25 ng/mL) and comparable to values obtained in baboon and man using [(11)C]flumazenil PET (10 and 5.8 ng/mL, respectively). TPA023B was anxiolytic in rodent and primate (squirrel monkey) models of anxiety (elevated plus maze, fear-potentiated startle, conditioned suppression of drinking, conditioned emotional response) yet had no significant effects in rodent or primate assays of ataxia and/or myorelaxation (rotarod, chain-pulling, lever pressing), up to doses (10 mg/kg) corresponding to occupancy of greater than 99%. In man, TPA023B was well tolerated at a dose (1.5 mg) that produced occupancy of >50%, suggesting that the sedation previously seen with MRK-409 is due to the partial agonist efficacy of that compound at the α1 subtype, and highlighting the importance of antagonist efficacy at this particular GABA(A) receptor population for avoiding sedation in man.

Transplacental transfer of anthracyclines, vinblastine, and 4-hydroxy-cyclophosphamide in a baboon model.

OBJECTIVE: The paucity of data on the fetal effects of prenatal exposure to chemotherapy prompted us to study transplacental transport of chemotherapeutic agents. METHODS: Fluorouracil-epirubicin-cyclophosphamide (FEC) and doxorubicin-bleomycin-vinblastine-dacarbazine (ABVD) were administered to pregnant baboons. At predefined time points over the first 25 h after drug administration, fetal and maternal blood samples, amniotic fluid (AF), urine, fetal and maternal tissues, and cerebrospinal fluid (CSF) were collected. High-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS) were used for bioanalysis of doxorubicin, epirubicin, vinblastine, and cyclophosphamide. RESULTS: In nine baboons, at a median gestational age of 139 days (range, 93-169), FEC 100% (n = 2), FEC 200% (n=1), ABVD 100% (n = 5), and ABVD 200% (n = 1) were administered. The obtained ratios of fetal/maternal drug concentration in the different simultaneously collected samples were used as a measure for transplacental transfer. Fetal plasma concentrations of doxorubicin and epirubicin averaged 7.5 ± 3.2% (n = 6) and 4.0 ± 1.6% (n = 8) of maternal concentrations, respectively. Fetal tissues contained 6.3 ± 7.9% and 8.7 ± 8.1% of maternal tissue concentrations for doxorubicin and epirubicin, respectively. Vinblastine concentrations in fetal plasma averaged 18.5 ± 15.5% (n=9) of maternal concentrations. Anthracyclines and vinblastine were neither detectable in maternal nor in fetal brain/CSF. 4-Hydroxy-cyclophosphamide concentrations in fetal plasma and CSF averaged 25.1 ± 6.3% (n = 3) and 63.0% (n = 1) of the maternal concentrations, respectively. CONCLUSION: This study shows limited fetal exposure after maternal administration of doxorubicin, epirubicin, vinblastine, and 4-hydroxy-cyclophosphamide.

Does the unfavorable pharmacokinetic and pharmacodynamic profile of the iNOS inhibitor GW273629 lead to inefficacy in acute migraine?

The objective of this study was to investigate the pharmacodynamics and pharmacokinetics of a single dose of GW273629, a selective iNOS inhibitor, given during and outside a migraine attack. GW273629 1500 mg was administered to 15 migraine patients both ictally and interictally. Nasal and exhaled nitric oxide (NO), plasma 3-nitrotyrosine, and nitrates were measured to assess systemic NO production. In addition, pharmacokinetics and treatment response were assessed. Data are mean (95% confidence interval [CI]). Plasma 3-nitrotyrosine was higher ictally: 11.96 (8.22, 15.71) ictally versus 2.74 (2.24, 3.24) ng/10 mg interictally (P < .0001). Exhaled and nasal NO showed a similar trend: 12.5 (6.5, 18.6) and 62.2 (41.5, 82.8) ppb ictally versus 9.9 (6.3, 13.4) ppb and 52.5 (38.5, 66.0) ppb interictally, respectively. Early absorption of GW273629 (AUC(0-2) [90% CI]) was reduced by 41 (22, 55)% during an attack. There was no improvement of headache or associated symptoms. Migraine headache is associated with reduced early absorption of GW273629 and excess NO production. In this open-label study, GW273629 was ineffective in the treatment of acute migraine.

Determinants of variability in clearance of exogenous compounds in neonates.

Although the general principles of disposition and elimination of exogenous compounds apply in neonates, their specific characteristics warrant a tailored approach. Children display maturation in drug disposition, and these maturational changes are most prominent in the first year of life. Elimination clearance is mainly either through metabolic or renal elimination clearance. Almost all phase I and phase II metabolic processes display ontogeny in a iso-enzyme specific pattern. Variation in phenotypic metabolic clearance is based on constitutional, environmental and genetics factors. In early life, it mainly reflects ontogeny, but other covariates may also become relevant. The impact of various covariates like postmenstrual age, postnatal age, disease state characteristics and polymorphisms are illustrated based or 'probe' drugs (paracetamol, tramadol, propofol) administered as part of their medical treatment in critically ill neonates. Renal elimination clearance in early life is low and almost completely depends on glomerular filtration. Despite this overall low clearance, interindividual variability is already extensive and can be explained by covariates like postmenstrual age, postnatal age, co-administration of a non-selective cyclo-oxygenase inhibitor or growth restriction. These findings are illustrated by observations on amikacin, vancomycin and cefazolin disposition in perinatal life. These maturational changes all have impact on the pharmaco/toxicokinetics and -dynamics. We hereby would like to extent the adagio of Paracelsus that 'all is toxic, it only depends on the dose' by making the point that the 'patient' is also relevant.

Urinary propofol metabolites in early life after single intravenous bolus.

BACKGROUND: /st> Propofol clearance is lower in neonates than in adults and displays extensive interindividual variability, in part explained by postmenstrual age (PMA) and postnatal age (PNA). Since propofol is almost exclusively cleared metabolically, urinary propofol metabolites were determined in early life and compared with similar observations reported in adults. METHODS: /st> Twenty-four hours urine collections were sampled after a single i.v. bolus of propofol (3 mg kg(-1)) in neonates undergoing procedural sedation. Clinical characteristics (PMA, PNA, weight, and cardiopathy) were recorded. Urine metabolites [propofol glucuronide (PG), 1- and 4-quinol glucuronide (QG)] were quantified using high-pressure liquid chromatography. Urine recovery (% administered dose) and the contribution of PG and QG to urinary elimination were calculated. Data were reported by median and range, analysed by Mann-Whitney U or Spearman's rank. RESULTS: /st> Eleven neonates (median PNA 11 days, PMA 38 weeks) were included. Median propofol metabolite recovery was 64% (range 34-98%). PG contributed 34% (range 8-67%) and QG 65% (range 33-92%). There was no significant correlation between either PMA, PNA, or cardiopathy and propofol metabolites. Compared with adults, the contribution of PG (34% vs 77%) was lower and the contribution of QG (65% vs 22%) was higher in neonates. CONCLUSIONS: /st> Propofol metabolism in neonates differs from adults, reflecting the age-dependent limited glucuronidation capacity. Hydroxylation to quinol metabolites already contributes to propofol metabolism. These differences likely explain the PMA- and PNA-dependent reduced propofol clearance in neonates.