The Pharmacokinetics of Caffeine in Preterm Newborns: No Influence of Doxapram but Important Maturation with Age

Background: Apnea of prematurity can persist despite caffeine therapy in preterm infants. Doxapram may additionally support breathing. Although multiple small studies have reported the efficacy of doxapram, the structural co-treatment with caffeine impedes to ascribe the efficacy to doxapram itself or to a pharmacokinetic (PK) interaction where doxapram increases the exposure to caffeine. We examined whether there is a PK drug-drug interaction between doxapram and caffeine by developing a PK model for caffeine including infants with and without doxapram treatment. Methods: In preterm neonates receiving caffeine, we determined caffeine plasma concentrations before, during, and directly after doxapram co-treatment and used these to develop a population PK model in NONMEM 7.3. Patient characteristics and concomitant doxapram administration were tested as covariates. Results: 166 plasma samples were collected from 39 preterm neonates receiving caffeine (median gestational age 25.6 [range 24.0–28.0] weeks) of which 65 samples were taken during co-treatment with doxapram (39%, from 32/39 infants). Clearance of caffeine was 9.99 mL/h for a typical preterm neonate with a birth weight of 0.8 kg and 23 days postnatal age and increased with birth weight and postnatal age, resulting in a 4-fold increase in clearance during the first month of life. No PK interaction between caffeine and doxapram was identified. Discussion: Caffeine clearance is not affected by concomitant doxapram therapy but shows a rapid maturation with postnatal age. As current guidelines do not adjust the caffeine dose with postnatal age, decreased exposure to caffeine might partly explain the need for doxapram therapy after the first week of life.

P71 Population pharmacokinetics and pharmacogenetics of caffeine in Chinese premature infants with apnoea of prematurity

BackgroundCaffeine is commonly regarded as the treatment of choice for neonatal apnoea. However, limited data on the developmental pharmacokinetics and pharmacogenetics were available in Chinese premature infants. The objective of this study was to develop a population pharmacokinetic model of caffeine after intravenous administration to Chinese neonates with apnoea of prematurity (AOP) and evaluate the impact of developmental pharmacogenetics of CYP1A2.MethodsSparse pharmacokinetic samples were collected from AOP newborns receiving caffeine citrate at a loading dose of 20 mg/kg/d and maintenance dose of 5–10 mg/kg/d. Population pharmacokinetic-pharmacogenetic analysis of caffeine was performed using NONMEM. Eight CYP1A2 polymorphisms were genotyped.ResultsA total of 99 newborns with a mean (SD) postmenstrual age of 32.0 (2.16) (range 22.3 - 38.0) weeks were included in the present study. Pharmacokinetic data fitted an one-compartment model with first-order absorption and elimination. Current weight, postmenstrual age and serum creatinine concentration were significant covariates influencing caffeine clearance. None of tested CYP1A2 polymorphisms had significant impact on caffeine pharmacokinetics.ConclusionThe population pharmacokinetics-pharmacogenetics of caffeine was evaluated in Chinese AOP premature infants. This developmental pharmacokinetic model can be helpful to individualize caffeine therapy.Disclosure(s)Nothing to disclose

Correlation Between Red Blood Cell Survival and Cytochrome P450 1A2 Enzyme Activity

Background Autologous red blood cell (RBC) 24h recovery in healthy volunteers is known to be highly variable between subjects, but repeatable within subjects. We previously performed metabolic screening on 2 subjects (HR) with consistently high historical 24h recoveries (85%, 88%) and 2 subjects (LR) with lower recoveries (74%, 74%). We observed that the HR subjects had lower RBC caffeine levels than the grand average for the study, while LR subjects had higher levels. Because these differences were not explained by the subjects’ self-reported caffeine consumption, we hypothesized that they may be due to differences in caffeine metabolism and clearance that correlate with RBC survival following storage and transfusion Caffeine (1,3,7-trimethylxanthine - 137X ) is demethylated by cytochrome P450 1A2 (CYP1A2) to form 81.5% paraxanthine (1,7-dimethylxanthine -17X), 5.4% theophylline, and 10.8% theobromine. Single nucleotide polymorphisms (SNPs) in CYP1A2 results in variation in enzyme activity. Polymorphisms in the aromatic hydrocarbon receptor (AHR) may also affect caffeine clearance. Caffeine clearance is the gold standard assay for in vivo determination of CYP1A2 activity, and a 4 hour point estimate may be obtained using the plasma 17X/137X ratio following caffeine challenge. Methods We performed focused genotyping of the 4 index subjects for 3 CYP1A2 SNPs (rs762551, rs24708932, and rs2472297) and 2 AHR SNPs (rs6968865 and rs4410790), all previously reported as affecting caffeine metabolism. DNA was extracted from whole blood and SNP genotyping performed using real time PCR with Taqman probes on the AB 7500 FAST system. Caffeine metabolic clearance was determined in 3 of 4 index subjects by a controlled challenge. 100mg caffeine PO was administered in apple juice to subjects that had abstained from caffeine for 24h. Venous blood was obtained pre and 4h post caffeine administration. Plasma was separated and frozen within 2h of collection. Caffeine and metabolites were quantified by liquid chromatography-mass spectrometry (LC-MS) with isotopically labeled internal standards. The single point clearance rate of caffeine was estimated as the ratio of the 4h difference from baseline in (17x+theophiline):caffeine. Results The one HR who could be recalled for caffeine challenge had the highest 4h caffeine metabolic clearance ratio; the two LR subjects had lower ratios (see Table). HR were homozygous (A/A) for CYP1A2 rs762551, while the 2 LR subjects were heterozygous (A/C) for CYP1A2 rs762551. The correlations between SNP results and caffeine clearance agree with known CYP1A2 activities for these genotypes. Other CYP1A2 and AHR SNPs did not partition with the RBC recoveries, caffeine levels or caffeine metabolic ratios. Conclusion In a small number of subjects (n-=2 from each group), historical in vivo RBC recovery was observed to be associated with peripheral blood caffeine levels, caffeine metabolic clearance, and known functional polymorphisms in the CYP1A2 gene. In the event that these associations persist upon subsequent studies with more participants, then additional trials will be needed to test if the caffeine (or its metabolites) has a direct effect upon RBCs or if caffeine clearance is a surrogate marker of CYP1A2 function or activity of other metabolic pathways that can regulate RBC survival after storage and transfusion. Disclosures: Zimring: Immucor Inc.: Research Funding; Terumo: Research Funding; Haemonetics: Consultancy; Cerus: Honoraria.

Drug Interactions with Clinafloxacin

ABSTRACT Many fluoroquinolone antibiotics are inhibitors of cytochrome P450 enzyme systems and may produce potentially important drug interactions when administered with other drugs. Studies were conducted to determine the effect of clinafloxacin on the pharmacokinetics of theophylline, caffeine, warfarin, and phenytoin, as well as the effect of phenytoin on the pharmacokinetics of clinafloxacin. Concomitant administration of 200 or 400 mg of clinafloxacin reduces mean theophylline clearance by approximately 50 and 70%, respectively, and reduces mean caffeine clearance by 84%. (R)-Warfarin concentrations in plasma during clinafloxacin administration are 32% higher and (S)-warfarin concentrations do not change during clinafloxacin treatment. An observed late pharmacodynamic effect was most likely due to gut flora changes. Phenytoin has no effect on clinafloxacin pharmacokinetics, while phenytoin clearance is 15% lower during clinafloxacin administration.