During pregnancy, there are changes in distribution volume due to changes in body composition, in metabolic activity affecting drug metabolism and in renal elimination (GFR, tubular) capacity. Consequently, pregnancy warrants a focussed approach in clinical pharmacology, since these important alterations in physiology (e.g. renal, hepatic, metabolism, body composition) affect drug disposition. Despite these differences, even commonly administered drugs like non-opioids have not been evaluated on their pharmacokinetics during pregnancy. We report on our observations on paracetamol and ketorolac disposition following caesarean delivery to illustrate the feasibility and relevance of such focussed studies. Key-Words: pregnancy – pharmacokinetics – paracetamol – ketorolac – multimodal analgesia 1. multimodal analgesia at delivery A drug is administered with the intention to obtain a dose-related therapeutic effect, preferably without side-effects. Clinical pharmacology aims to predict these effects based on drug, population and/or patientspecific pharmacokinetics (PK, concentrationtime) and -dynamics (PD, concentration-effect). Pregnancy, labour and postpartum warrant a focussed approach [1,2,3]. Renal clearance is enhanced during pregnancy (i.e. higher glomerular filtration rate, higher active tubular excretion), the metabolic activity (e.g. oxygen consumption, cardiac output) is also increased often resulting in increased metabolic drug clearance (phase I and phase II), although alterations are in part iso-enzyme specific. Rarely, iso-enzyme specific activity (e.g. CYP1A2 and CYP2C19) is decreased during pregnancy through oestrogen mediated inhibition [2,3]. Finally, changes in body weight or binding capacity (protein changes, pH shifts) affect drug distribution. Duration of pregnancy (gestational age), co-morbidity (e.g. preeclampsia) or labour itself further modulate the variability in pharmacokinetics [1,2,3]. These PK alterations can subsequently affect the variability in the observed drug response, including the level of analgesia. The interindividual variability in drug response is further affected by between individual differences in PD covariates. When applied to post caesarean pain management, the presence of labour but also aspects related to individual thermal pain thresholds, personality characteristics or the duration of surgery further modulate the interindividual variability in pain reported and analgesics administered post caesarean [4,5]. Multimodal analgesia following caesarean should focus on effective pain relief so that the mother can mobilise early, but she also has the added responsibility of needing to care for her newborn [3,4]. There is no single ‘magic bullet’ for postoperative pain management following caesarean. The options are extensive and are at least in part driven by availability, preferences, experience, resource limitations and costs. Most methods rely on opioids, supplemented with nerve blocks, adjunctive techniques, and antiinflammatory analgesics, including intravenous (iv) paracetamol or ketorolac [3,4,5]. Despite the fact that both compounds are routinely used as part of multimodal analgesia, there are no PK observations to suggest dosing regimens. Commonly, dosing is similar to other postoperative analgesia indications, without taking the impact of pregnancy on the clinical pharmacology of these compounds into Recent Researches in Medicine and Medical Chemistry ISBN: 978-1-61804-111-1 95 account. In a stepwise approach to improve multimodal analgesia after caesarean, we aim to describe iv paracetamol and iv ketorolac PK. 2 iv paracetamol PK at delivery Pregnancy and postpartum affect drug disposition, but data on iv paracetamol loading dose pharmacokinetics at delivery have not been reported. We aimed to describe loading dose pharmacokinetics of intravenous paracetamol following surgical delivery and to compare these postpartum observations with similar observations as reported in young female volunteers [5,6]. Shortly following caesarean section, women received a loading dose (2 g) of IV paracetamol and 4 (1,2,4 and 6 h) plasma samples were collected. Individual pharmacokinetics were calculated assuming a linear one compartment model with instantaneous input, first order output and compared with similar observations (2 g IV loading dose, same time points) reported in 14 young female volunteers [6,7]. Observations were reported by median and range, compared by Mann-Whitney U test. Observations were available in 42 cases, 28 following caesarean section. Median paracetamol plasma concentrations after 1, 2, 4 and 6 hours following operative delivery were 22.5, 15.25, 7.9, and 3.9 mg/l. In healthy volunteers, median concentrations were 31.5, 21.3, 10.9, and 5 mg/l respectively (all at least p<0.01). Median clearance (15.5 vs 20.3 l/h, p<0.01) and distribution volume (43.7 vs 58.3 L, p<0.001) were significantly higher post caesarean section. Even after correction for body surface area, this increase (9.6 vs 10.9 l/h.m 3 ) remained significant (p<0.05) (figure 1). Fig 1: paracetamol clearance (l/h) in healthy volunteers or at delivery p a ra c e ta m o l c le a ra n c e ( L /h ) 0 10 20 30 40 50 60 70 healthy volunteers post cesarean Following caesarean delivery, paracetamol clearance (+35%) and distribution volume (+30%) are increased compared to healthy adult volunteers. Finally, the between individual variability in paracetamol clearance is significantly higher at delivery (4-fold instead of 2-fold), suggesting that there are other covariates besides weight changes involved at delivery. To further explore this, we evaluated the impact of gestational age at delivery on the individual clearance estimates. In a scatter diagraph, it seems that there is an overall higher clearance throughout pregnancy, with a subsequent reduction at term age. (figure 2) Fig. 2: scatter diagram: individual clearance (l/h.m 2 ) on gestational age (weeks). 25 30 35 40 45 5 10 15 20 25 30 GA c le a ra n c e /b s a 3 iv ketorolac PK at delivery Ketorolac tromethamine is administered by iv route as part of a multimodal analgesia protocol after cesarean [5], but data on ketorolac pharmacokinetics (PK) at delivery are absent. The aim was to estimate ketorolac PK postcesarean and compare these values with estimates in non-pregnant adult volunteers [8]. Women who underwent a cesarean section and received an iv dose of 30 mg ketorolac shortly after delivery of the newborn, were included in this open-label PK study. Blood samples were collected 1, 2, 4, 6 and 8 hours after ketorolac administration. Racemic ketorolac was quantified by HPLC with UV detection and PK were calculated assuming a linear one compartment model with instantaneous input and first order output [7]. The distribution volume (Vd, l and l/kg) and concentration at t = 0 (Cmax0) were calculated. The slope of the Recent Researches in Medicine and Medical Chemistry ISBN: 978-1-61804-111-1 96 curve was used to calculate time constant K, elimination half life, and clearance [7]. Individual PK estimates were calculated in 39 cases (12 delivered preterm, < 37 weeks). Median weight at delivery was 73.2 (range 40106) kg. Median distribution volume was 0.23 (range 0.16-0.42) l/kg, elimination half life 2.41 (1.26-4.75 h), clearance 5.2 (2.25-15.60) l/h and 0.069 (0.027-0.163) l/kg/h respectively. There were no significant differences in PK estimates between term and preterm cases (0.23 vs 0.22 l/kg, 2.40 vs 2.38 h, 5.22 vs 4.95 l/h, 0.068 vs 0.069 l/kg/h). When compared to data as published in healthy non-pregnant adults, clearance (0.069 vs 0.018-0.033 l/kg/h) seems to be higher (2 fold) at delivery compared to the non-pregnant setting [8]. 4. Discussion and conclusions Clinical pharmacology aims to predict effects based on drug, population and/or patientspecific pharmacokinetics (PK, concentrationtime) and -dynamics (PD, concentration-effect) [1,2,3]. Understanding this dose-exposure and dose-response relationship remains a major challenge for clinicians to optimize safety and efficacy when drugs are administer. This is even more pronounced in specific populations like pregnant women. In the present case studies, we illustrated the impact of pregnancy on paracetamol and ketorolac pharmacokinetics. Although subsequent extrapolation of these PK observations to PD needs extensive prospective evaluation, these findings do suggest that higher doses (either shorter time interval between consecutive doses or higher doses) should be

Physiological changes during pregnancy and in early life result in alterations in pharmacokinetics (PK) and pharmacodynamics (PD). Cefazolin (CFZ) is a frequently administered drug, also in special populations as pregnant woman and neonates, but PK data in these patients are limited. We aimed to focus on CFZ disposition in these two special patient groups. CFZ protein binding saturability was hereby established in both cohorts, however neonates display a markedly higher unbound CFZ fraction compared to adults. CFZ clearance (Cl) during pregnancy is twice as high as in the normal setting and clearance in neonates is lower compared to older children. To compare our data with other ‘special’ populations, we provided an overview of recalculated CFZ volume of distribution (Vd) and Cl values from reported datasets in literature. Key-Words: cefazolin – protein binding – pharmacokinetics – pregnancy – newborn – clearance

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.

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.

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.