Developmental Pharmacokinetics and Safety of Ibuprofen and Its Enantiomers in the Conventional Pig as Potential Pediatric Animal Model

Millecam, Joske; Bergen, Thomas van; Schauvliege, Stijn; Antonissen, Gunther; Martens, Ann; Chiers, Koen; Gehring, Ronette; Gasthuys, Elke; Walle, Johan Vande; Croubels, Siska; Devreese, Mathias

doi:10.3389/fphar.2019.00505

Cited by 18 publications

(16 citation statements)

References 39 publications

(58 reference statements)

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“…It should be noted, however, that the lower AUC ratio for 2OH-IBU and COOH-IBU in the 6- to 7-month-old pigs could also be attributed to the much higher AUC of IBU. This higher AUC might be a consequence of the lower V d in the 6- to 7-month-old pigs compared to younger pigs, as has been demonstrated by Millecam et al, (2019). As can be seen from Table 1 , the C 0 of IBU after IV administration was indeed significantly higher compared to the other age categories, pointing towards a lower V d .…”

Section: Discussionmentioning

confidence: 51%

“…The total IBU concentrations were determined as the sum of R- and S-IBU using a validated ultra performance liquid chromatography with an ultraviolet detector (UPLC-UV) method according to Millecam et al (2019). IBU metabolites were quantified using an in-house developed and validated ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS) method.…”

Section: Methodsmentioning

confidence: 99%

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In Vivo Metabolism of Ibuprofen in Growing Conventional Pigs: A Pharmacokinetic Approach

2019

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The juvenile conventional pig has been suggested as a preclinical animal model to evaluate pharmacokinetic (PK), pharmacodynamic (PD), and safety parameters in children. However, a lot of developmental changes in pig physiology still need to be unraveled. While the in vitro ontogeny of pig biotransformation enzymes is getting more attention in literature, the in vivo developmental changes have not yet been investigated. Therefore, the aim of the current study was to evaluate the biotransformation of ibuprofen (IBU) in conventional pigs aged 1 week, 4 weeks, 8 weeks, and 6–7 months after a single intravenous and oral administration of 5 mg/kg body weight (BW) of IBU, using a PK approach in a crossover design for each age group. An ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS) method was developed and validated to determine 2-hydroxyibuprofen (2OH-IBU), carboxyibuprofen (COOH-IBU), and ibuprofen glucuronide (IBU-GlcA) in pig plasma. All three metabolites could be quantified in plasma and the following PK parameters were determined: C max , T max , AUC 0→6h , area under plasma concentration–time curve (AUC) ratio between parent drug and metabolite, and the absolute oral bioavailability of the parent drug IBU. The plasma concentrations of the metabolites were always lower than those of IBU. The bioavailability was high, indicating limited pre-systemic biotransformation. The AUC ratio of 2OH-IBU and COOH-IBU/IBU showed a significant increase at 4 weeks of age compared to the 1-week-old and 6- to 7-month-old pigs. Interestingly, the IBU-GlcA/IBU AUC ratio did not change with age. The present study demonstrated that the main metabolites of IBU in human are also present in growing pigs. The oxidative phase I metabolism of IBU in growing conventional pigs did change with age. In contrast, age did not seem to affect the glucuronidation capacity of IBU in conventional pigs, although more studies with other substrate drugs are needed to confirm this.

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Section: Discussionmentioning

confidence: 51%

Section: Methodsmentioning

confidence: 99%

In Vivo Metabolism of Ibuprofen in Growing Conventional Pigs: A Pharmacokinetic Approach

2019

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“…Despite this limited data we were able to confirm a higher CL R compared to CL S , as also observed in other preterm neonates and older populations (Figure 2). 10,11,34–36 The limited data available can also explain the lack of identification of chiral inversion of R‐ to S‐ibuprofen, as identified in piglets and well described in adults 7,13 . However, the varying fractions of R‐ibuprofen dose to be inverted identified by Gregoire et al (17 and 61%) already suggested difficulties with identifying this inversion in preterm neonates.…”

Section: Discussionmentioning

confidence: 99%

Enantiomer specific pharmacokinetics of ibuprofen in preterm neonates with patent ductus arteriosus

Engbers

Flint

Völler

et al. 2020

Brit J Clinical Pharma

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Aims Racemic ibuprofen is widely used for the treatment of preterm neonates with patent ductus arteriosus. Currently used bodyweight‐based dosing guidelines are based on total ibuprofen, while only the S‐enantiomer of ibuprofen is pharmacologically active. We aimed to optimize ibuprofen dosing for preterm neonates of different ages based on an enantiomer‐specific population pharmacokinetic model. Methods We prospectively collected 210 plasma samples of 67 preterm neonates treated with ibuprofen for patent ductus arteriosus (median gestational age [GA] 26 [range 24–30] weeks, median body weight 0.83 [0.45–1.59] kg, median postnatal age [PNA] 3 [1–12] days), and developed a population pharmacokinetic model for S‐ and R‐ibuprofen. Results We found that S‐ibuprofen clearance (CLS, 3.98 mL/h [relative standard error {RSE} 8%]) increases with PNA and GA, with exponents of 2.25 (RSE 6%) and 5.81 (RSE 15%), respectively. Additionally, a 3.11‐fold higher CLS was estimated for preterm neonates born small for GA (RSE 34%). Clearance of R‐ibuprofen was found to be high compared to CLS (18 mL/h [RSE 24%]), resulting in a low contribution of R‐ibuprofen to total ibuprofen exposure. Current body weight was identified as covariate on both volume of distribution of S‐ibuprofen and R‐ibuprofen. Conclusion S‐ibuprofen clearance shows important maturation, especially with PNA, resulting in an up to 3‐fold increase in CLS during a 3‐day treatment regimen. This rapid increase in clearance needs to be incorporated in dosing guidelines by adjusting the dose for every day after birth to achieve equal ibuprofen exposure.

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“…Kearns & Reed report that Phase I hepatic transformation (eg, CYP2C) progressively increases to near adult values by 6 months of age . Further support for a maturation profile that is rapid comes from infant pigs (1 week, 4 weeks, 8 weeks, 6 months) that were used to investigate ibuprofen developmental pharmacokinetics . Peak clearance estimates (5.6 mL/min/kg) were in piglets aged 8 weeks.…”

Section: Discussionmentioning

confidence: 99%

A target concentration strategy to determine ibuprofen dosing in children

Anderson

Hannam

2019

Pediatric Anesthesia

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Background Ibuprofen is widely used for ductus arteriosus closure in premature neonates and for analgesia in children and adults. There are no maturation descriptors of clearance. This lack of maturation understanding limits dosing recommendations from premature neonates to adulthood. Methods Published clearance estimates from different aged patients determined after administration from time‐concentration profiles were used to construct a maturation model based on size and age. Curve fitting was performed using nonlinear mixed‐effects models. A target concentration strategy was used to estimate maintenance dose at different ages. Results There were three publications reporting an estimate of individual clearance estimates in premature neonates, three reporting population clearances in infants, 11 in children 2‐15 years (1 with individual and 9 with population clearances), and 13 adult studies (1 with individual and 12 with population clearances). Clearance maturation, standardized to a 70 kg person was described using the Hill equation. Mature clearance was 3.81 (CV 15.5%, 95%CI 3.72, 3.92) L/h/70 kg. The maturation half‐time was 36.8 (CV 9.2%, 95%CI 34.7, 40.9) weeks postmenstrual age and the Hill coefficient 11.5 (95%CI 8.1, 15). A target effect of four units (visual analogue scale 0‐10) correlated with an effect site concentration of 6.3 mg/L: a concentration achieved at trough after 400 mg 8 hourly in adults. Conclusion Previously published pharmacokinetic parameters can be used to develop maturation models that address gaps in current knowledge regarding the influence of age on a drug's disposition. Maturation of ibuprofen clearance was rapid and was 90% of adult values by the first month of life in term neonates (ie, 44 weeks postmenstrual age) and 98% of standardized adult estimates by 3 months of age (53 weeks postmenstrual age). Clearance informed dosing predictions in all ages (premature neonate to adult) and matched those doses in common use in children older than 3 months.

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Developmental Pharmacokinetics and Safety of Ibuprofen and Its Enantiomers in the Conventional Pig as Potential Pediatric Animal Model

Cited by 18 publications

References 39 publications

In Vivo Metabolism of Ibuprofen in Growing Conventional Pigs: A Pharmacokinetic Approach

In Vivo Metabolism of Ibuprofen in Growing Conventional Pigs: A Pharmacokinetic Approach

Enantiomer specific pharmacokinetics of ibuprofen in preterm neonates with patent ductus arteriosus

A target concentration strategy to determine ibuprofen dosing in children

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