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The antidiabetic drug gliclazide is partly metabolized by CYP2C19, the main enzyme involved in omeprazole metabolism. The aim of the study was to explore the interaction between omeprazole and gliclazide in relation to CYP2C19 phenotype using physiologically based pharmacokinetic (PBPK) modeling approach. Developed PBPK models were verified using in vivo pharmacokinetic profiles obtained from a clinical trial on omeprazole-gliclazide interaction in healthy volunteers, CYP2C19 normal/rapid/ultrarapid metabolizers (NM/RM/UM). In addition, the association of omeprazole cotreatment with gliclazide-induced hypoglycemia was explored in 267 patients with type 2 diabetes (T2D) from the GoDARTS cohort, Scotland. The PBPK simulations predicted 1.4–1.6-fold higher gliclazide area under the curve (AUC) after 5-day treatment with 20 mg omeprazole in all CYP2C19 phenotype groups except in poor metabolizers. The predicted gliclazide AUC increased 2.1 and 2.5-fold in intermediate metabolizers, and 2.6- and 3.8-fold in NM/RM/UM group, after simulated 20-day dosing with 40 mg omeprazole once and twice daily, respectively. The predicted results were corroborated by findings in patients with T2D which demonstrated 3.3-fold higher odds of severe gliclazide-induced hypoglycemia in NM/RM/UM patients concomitantly treated with omeprazole. Our results indicate that omeprazole may increase exposure to gliclazide and thus increase the risk of gliclazide-associated hypoglycemia in the majority of patients.

Aims Although ketorolac analgesia is linked only to the S-enantiomer, there is limited information on the stereo-selective pharmacokinetics of this agent. We studied the stereo-selective pharmacokinetics of ketorolac in a pooled dataset of two studies, with women at delivery and 4–5 months postpartum, and males and nonpregnant females. Methods Nonlinear mixed-effect modelling was used to evaluate the stereo-selective pharmacokinetics of ketorolac tromethamine after a single intravenous injection immediately after delivery (n = 41), 4–5 months postpartum (n = 8, paired), and in male (n = 12) and nonpregnant female (n = 14) subjects. All of the males and six of the nonpregnant females were recruited from another study, in which they were undergoing blood sampling for 24 h. All remaining cases underwent blood sampling for 8 h. Results For both the R- and S-enantiomers, body weight affected ketorolac clearance. In addition, clearance for both enantiomers was 36% [95% confidence interval (CI) 15%, 58%] higher in male than in female subjects of the same body weight, and 55% (95% CI 33%, 78%) higher in women at delivery than in nonpregnant women of the same body weight. Women at delivery also had a 27% (95% CI 8%, 46%) higher distribution volume than nonpregnant women. The proportional effects of the covariates were not significantly different for the two ketorolac enantiomers. Conclusions Besides the anticipated impact of body weight on clearance, R- and S-ketorolac clearance is increased in male subjects and in women at delivery. To reach an exposure equivalent to that in nonpregnant women, males should receive a 36% increased ketorolac dose and pregnant women a 55% increased dose, in addition to a dose adjustment by body weight.

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. ispartof: Bosnian Journal of Basic Medical Sciences vol:17 issue:1 pages:54-60 ispartof: location:Bosnia and Herzegovina status: published

Aminoglycosides pharmacokinetics (PK) is expected to change in neonates with perinatal asphyxia treated with therapeutic hypothermia (PATH). Several amikacin dosing guidelines have been proposed to treat neonates with (suspected) septicemia, however, none provide adjustments in the case of PATH. Therefore, we aimed to quantify the differences in amikacin PK between neonates with and without PATH to propose suitable dosing recommendations.Based on amikacin therapeutic drug monitoring data collected retrospectively from neonates with PATH, combined with a published dataset, we assessed the impact of PATH on amikacin PK using population modelling. Monte Carlo and stochastic simulations were performed to establish amikacin exposures in neonates with PATH after dosing according to the current guidelines and according to proposed model-derived dosing guidelines.Amikacin clearance was decreased by 40.6% in neonates with PATH, with no changes in volume of distribution. Simulations showed that, increasing the dosing interval with 12 hours results in a decrease in percentage of neonates reaching toxic trough levels (> 5 mg/L) from 40-76% to 14-25%, while still reaching efficacy targets, compared to current dosing regimens.Based on this study, a 12-hour increase in amikacin dosing interval in neonates with PATH is proposed to correct for the reduced clearance, yielding safe and effective exposures. As amikacin is renally excreted, further studies into other renally excreted drugs may be required as their clearance may also be impaired. ispartof: Antimicrobial Agents and Chemotherapy vol:61 issue:12 ispartof: location:United States status: published

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.

Although ketorolac analgesia is linked only to the S-enantiomer, there is limited information on the stereo-selective pharmacokinetics of this agent. We studied the stereo-selective pharmacokinetics of ketorolac in a pooled dataset of two studies, with women at delivery and 4-5 months postpartum, and males and nonpregnant females.Nonlinear mixed-effect modelling was used to evaluate the stereo-selective pharmacokinetics of ketorolac tromethamine after a single intravenous injection immediately after delivery (n = 41), 4-5 months postpartum (n = 8, paired), and in male (n = 12) and nonpregnant female (n = 14) subjects. All of the males and six of the nonpregnant females were recruited from another study, in which they were undergoing blood sampling for 24 h. All remaining cases underwent blood sampling for 8 h.For both the R- and S-enantiomers, body weight affected ketorolac clearance. In addition, clearance for both enantiomers was 36% [95% confidence interval (CI) 15%, 58%] higher in male than in female subjects of the same body weight, and 55% (95% CI 33%, 78%) higher in women at delivery than in nonpregnant women of the same body weight. Women at delivery also had a 27% (95% CI 8%, 46%) higher distribution volume than nonpregnant women. The proportional effects of the covariates were not significantly different for the two ketorolac enantiomers.Besides the anticipated impact of body weight on clearance, R- and S-ketorolac clearance is increased in male subjects and in women at delivery. To reach an exposure equivalent to that in nonpregnant women, males should receive a 36% increased ketorolac dose and pregnant women a 55% increased dose, in addition to a dose adjustment by body weight.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Propylene glycol is commonly used as an excipient in dose forms and is ingested by neonates when administering different drugs. • While propylene glycol is generally considered to be safe, toxic effects like bradycardia, lactic acidosis and convulsions have been reported. • Information on the pharmacokinetics of propylene glycol in neonates is lacking to provide insight into the possible risk of toxicity. WHAT THIS STUDY ADDS • This study describes the pharmacokinetics of propylene glycol in preterm and term neonates co-administered with paracetamol and phenobarbital. • A pharmacokinetic model was developed which identified birth weight and postnatal age as important covariates for clearance. • The model was used to simulate exposure to propylene glycol co-administered with both drugs. 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 (CLi= 0.0849 × {(bBW/2720)1.69× (PNA/3)0.201}). Volume of distribution scaled allometrically with current bodyweight (Vi= 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.

Drug disposition is altered by pregnancy and the peripartum period but data on intravenous ketorolac pharmacokinetics following caesarean delivery have not been previously reported.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.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, P0.05). 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, P0.05). No significant covariates of pharmacokinetic estimates, including gestational age, preterm vs. term, twin vs. singleton and maternal co-morbidity, were seen in Group IP.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 (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

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 6h. 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 6h were 22.5, 15.25, 7.9, and 3.9mg/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.

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.

In order to enhance the sensitivity and to develop a faster direct method for plasma and urine quantification of racemic ketorolac, its metabolites (p-hydroxy-ketorolac and ketorolac glucuronides) and ketorolac enantiomers, we developed an extraction procedure based on solid-phase extraction combined with specific and fast chromatographic separation. Extraction and chromatography resulted in cleaner chromatograms without interfering compounds. In both plasma and urine, linearity of the standard curves for racemic ketorolac and p-hydroxy-ketorolac was validated in the concentration range 0.025-10 mg L -1, while for ketorolac enantiomers in the concentration range 0.025-5 mg L-1. The lower limit of quantification was two times lower than in earlier described methods. The developed method was suitable for direct quantification of racemic ketorolac, p-hydroxy-ketorolac and ketorolac enantiomers in plasma and urine samples in women at delivery and in postpartum, enabling us to document significant intra-individual differences in pharmacokinetics between these physiological states. © 2014 Springer-Verlag. ispartof: Chromatographia vol:77 issue:3 pages:803-812 status: published

ispartof: Journal of Anaesthesiology, Clinical Pharmacology vol:28 issue:3 pages:409-410 ispartof: location:India status: published

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

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.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).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.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.

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.

This paper aims to describe our propylene glycol (PG) research project to illustrate the feasibility and the difficulties encountered to perform excipient studies in neonates. PG is frequently co-administered excipient. PG accumulation potentially results in hyperosmolarity, lactic acidosis or hepato-renal toxicity in adults, reflecting issues related to pharmacokinetics (PKs) and -dynamics (PDs). Consequently, similar observations in neonates are urgently needed. Since newborns display ‘physiological’ impaired hepatic and renal elimination capacity, description of PG PK in neonates is warranted. The PG PD was assessed based on indicators of renal, hepatic and metabolic (in)tolerance earlier reported in adults and relating to osmolar changes. Based on the PK and PD data collected in neonates, we suggest that there is a lower limit of PG tolerance in neonates. In addition to preliminary data on PG disposition and tolerance in neonates, we mainly focus on the limitations of the current observations and the difficulties encountered during this PG project to further illustrate the specific setting of neonatal research.

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.

IntroductionIn this pooled study, we focused on the population pharmacokinetic profile of intravenous paracetamol metabolism and its covariates in young women, including during pregnancy and postpartum.MethodsPopulation PK parameters using non-linear mixed effect modelling were estimated in a pooled dataset of plasma and urine PK studies in 69 young women [47 at delivery, 8/47 again 10–15 weeks after delivery (early postpartum), and 7/8 again one year after delivery (late postpartum), 22 healthy female volunteers with or without oral contraceptives].ResultsPopulation PK parameters were estimated based on 815 plasma samples and 101 urine collections. Compared to healthy female volunteers (reference group) not on oral contraceptives, being at delivery was the most significant covariate for clearance to paracetamol glucuronide (F=2.03), while women in early postpartum had decreased paracetamol glucuronidation clearance (F=0.55). Women on contraceptives showed increased paracetamol glucuronidation clearance (F=1.46). The oestradiol level did not further affected this model. Being at delivery did not prove significant for clearance to paracetamol sulphate, but was higher in pregnant women who delivered preterm (ConclusionsCompared to healthy female volunteers, the urine paracetamol glucuronidation elimination in young women is affected by pregnancy (higher), early postpartum (lower) or exposure to oral contraceptives (higher). This may be of relevance to predict variability in glucuronidation activity in young women and to predict fetal exposure to paracetamol and its metabolites.

Background and aim Cefazolin (CFZ) is highly and saturably bound to albumin in adults. It is mainly used as prophylactic antibiotic agent. The aim of the present study is to describe CFZ protein binding and its covariates in neonates. Methods Neonates to whom intravenous CFZ (50 mg/kg) was administered as standard care prior to an invasive procedure were included. Total and unbound CFZ plasma concentrations were determined at ½; 2; 4 and 8 hours after CFZ administration. Linear and multiple regression analyses were used to document covariates of unbound CFZ fraction. For paired analysis of unbound CFZ fractions Wilcoxon signed rank test was used. Results Forty patients with median weight 2767 (range 830–4200) grams and median postmenstrual age (PMA) 39 (25–45) weeks were included. Median unbound CFZ fraction was 0.39 (0.10–0.73). Linear regression of unbound CFZ fraction versus unbound CFZ plasma concentration (R²=0.39) had a slope significantly different from zero (p Conclusions Between patient and within patient saturability of CFZ protein binding were also documented in neonates. We revealed a median plasma unbound CFZ fraction of 0.39 in neonates, which is higher than reported values in adults. The integration of CFZ protein binding aspects in future pharmacokinetic/pharmacodynamic research is warranted to optimize CFZ dosing, especially in neonates.

Introduction: Unintended propylene glycol (PG) administration (34 mg/kg/24h) did not affect postnatal adaptations [1]. Subsequently, we aim to document PG disposition in neonates. Methods: Blood and urine samples were collected in neonates to whom PG was co-administered (Paracetamol Synthetica®, Mendrisio, Italy). Plasma and urine samples were collected in the first six hours after the first drug administration (loading dose, 20 mg.kg1 paracetamol, equal to 16 mg PG kg-1). An earlier described reversed phase liquid chromatographic (LC) method with ultraviolet detection was optimized for chromatographic separation. Results: Chromatographic separation resulted in cleaner chromatograms without interfering compounds. Linearity, variations in the intra-and inter-assay precision and accuracy and stability at different temperature conditions were satisfactory. The lower limit of quantification (0.25 mg.L-1) was twenty times lower than in earlier described methods. The method was suitable for quantification of PG concentrations in low volume plasma (15-46 mg.L-1) and urine samples (20-175 mg.L-1), strongly indicating difference between neonates and adults in the relative contribution of the renal (7.02%) compared to the metabolic route for PG elimination. Assuming a one-compartment model, peak concentrations were around 40 mg.L-1, suggesting a distribution volume of 0.5 L.kg-1 while the elimination half life was estimated to be 6-12 h. Conclusion: An accurate and sensitive LC method was developed, and applied to determine PG in low volume neonate plasma and urine samples, enabling us to estimate the renal versus non-renal contribution of PG clearance in neonates.

Although the principles of drug disposition also apply in neonates, their specific characteristics warrant focussed assessment. Children display maturation in drug disposition, but this is most prominent in the first year of life. Besides maturational aspects of drug absorption and distribution, maturation mainly relates to (renal) elimination and (hepatic) metabolic clearance. Renal elimination clearance in early life is low and almost completely depends on glomerular filtration. Despite the overall low clearance, interindividual variability is already extensive and can be predicted by covariates like postmenstrual age, postnatal age, co-administration of a non-selective cyclo-oxygenase inhibitor, growth restriction or peripartal asphyxia. These findings are illustrated by observations on amikacin and vancomycin. Variation in phenotypic metabolic clearance is based on constitutional, environmental and genetic characteristics. In early life, it mainly reflects ontogeny, but other covariates may also become relevant. Almost all phase I and phase II metabolic processes display ontogeny in a iso-enzyme specific pattern. The impact of 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. The description of a compound specific pattern is beyond compound specific relevance. The maturational patterns described and the extent of the impact of covariates can subsequently be applied to predict in vivo time-concentration profiles for compounds that undergo similar routes of elimination. Through improved predictability, such maturational models can serve to improve both the clinical care and feasibility and safety of clinical studies in neonates.

BACKGROUND: There is relevant between individual variability in paracetamol clearance in young women. In this pooled study, we focused on the population pharmacokinetic profile of intravenous paracetamol metabolism and its covariates in young women. METHODS: Population PK parameters using non-linear mixed effect modelling were estimated in a pooled dataset of plasma and urine PK studies in 69 young women [47 at delivery, 8/47 again 10-15 weeks after delivery (early postpartum), and 7/8 again 1 year after delivery (late postpartum), 22 healthy female volunteers with or without oral contraceptives]. RESULTS: Population PK parameters were estimated based on 815 plasma samples and 101 urine collections. Compared to healthy female volunteers (reference group) not on oral contraceptives, being at delivery was the most significant covariate for clearance to paracetamol glucuronide (Factor = 2.03), while women in early postpartum had decreased paracetamol glucuronidation clearance (Factor = 0.55). Women on contraceptives showed increased paracetamol glucuronidation clearance (Factor = 1.46). The oestradiol level did not further affect this model. Being at delivery did not prove significant for clearance to paracetamol sulphate, but was higher in pregnant women who delivered preterm (

Background and purpose of the studyPropylene glycol (PG) is a frequently co-administered solvent in formulations administered to neonates, but reports on its (in)tolerance are limited. We aimed to report on renal, metabolic and hepatic tolerance before, during and following intravenous (iv) PG-paracetamol exposure and compared these data with similar datasets reported in literature on neonates exposed to PG without paracetamol or paracetamol without PG.MethodsRenal (diuresis, creatinemia, sodium), metabolic (Base Excess, Anion Gap, lactate, bicarbonate) and hepatic (liver enzymes, bilirubinemia) indicators before, during and following iv paracetamol-PG exposure in neonates as included in the PARANEO (paracetamol inneonates) study (intra-individual trends, ANOVA) were collected and analysed. Comparison with observations collected in cases exposed to either iv phenobarbital-PG or iv paracetamol-mannitol (inter-individual comparison, Mann Whitney-Utest) were made.ResultsPG exposure (median 34.1 mg/kg/24 h) did not affect postnatal renal, metabolic and hepatic adaptations in 60 cases exposed to paracetamol-PG. These indicators were similar when compared to 29 cases exposed to phenobarbital-PG or 172 cases exposed to paracetamol-mannitol.Major conclusionBased on observations in 89 neonates, low dose PG exposure was tolerated well. Studies on PG pharmacokinetics and its covariates are needed to estimate the upper level of PG tolerance in neonates.