Shirish Yakkundi

Risk assessment of neonatal excipient exposure: Lessons from food safety and other areas

Newborn babies can require significant amounts of medication containing excipients intended to improve the drug formulation. Most medicines given to neonates have been developed for adults or older children and contain excipients thought to be safe in these age groups. Many excipients have been used widely in neonates without obvious adverse effects. Some excipients may be toxic in high amounts in which case they need careful risk assessment. Alternatively, it is conceivable that ill-founded fears about excipients mean that potentially useful medicines are not made available to newborn babies. Choices about excipient exposure can occur at several stages throughout the lifecycle of a medicine, from product development through to clinical use. Making these choices requires a scalable approach to analysing the overall risk. In this contribution we examine these issues.

Development and validation of a method for the confirmation of halofuginone in chicken liver and eggs using electrospray tandem mass spectrometry

A method is described for the quantitative confirmation of halofuginone (HFG) residues in chicken liver and eggs. This method is based on LC coupled to positive ion electrospray MS-MS of the tissue extracts, prepared by trypsin digestion of the tissues followed by liquid-liquid extraction and final clean-up using Solid Phase Extraction (SPE). The [M+H](+) ion at m/z 416 is monitored along with four transitions at m/z 398, 138, 120 and 100. The method has been validated according to the draft EU criteria for the analysis of veterinary drug residues at 15, 30 and 45 microg kg(-1) in liver and 5, 15 and 50 microg kg(-1) in eggs. The new analytical limits, CCalpha and CCbeta were calculated for liver and were 35.4 and 43.6 microg kg(-1), respectively.

Development and validation of a dried blood spot LC-MS/MS assay to quantify ranitidine in paediatric samples.

A novel approach has been developed to determine ranitidine in paediatric samples using dried blood spots (DBS) on Guthrie cards (Whatman 903). A selective and sensitive HPLC-MS/MS assay has been developed and validated using small volumes of blood (30 μl). A 6 mm disc was punched from each DBS and extracted with methanolic solution of the internal standard (IS) nizatidine. This was further subjected to solid phase extraction (SPE), followed by reversed phase HPLC separation, using a XBridge™ C18 column and mobile phase 10 mM ammonium acetate/methanol (98:2 v/v) with a flow rate of 0.3 mL/min. This was combined with multiple reaction monitoring (MRM) mass detection using electrospray ionisation (ESI). The calibration curve for ranitidine was found linear over the range 10-500 ng/mL (r=0.996). The limit of quantification (LOQ) of the method was validated at 10 ng/mL. Accuracy and precision values for within and between days were <20% at the LOQ and <15% at all other concentrations. The validated DBS method was successfully applied to a clinical study employing 81 samples from 36 paediatric patients.

Prophylactic ranitidine treatment in critically ill children - a population pharmacokinetic study

AIMS To characterize the population pharmacokinetics of ranitidine in critically ill children and to determine the influence of various clinical and demographic factors on its disposition. METHODS Data were collected prospectively from 78 paediatric patients (n = 248 plasma samples) who received oral or intravenous ranitidine for prophylaxis against stress ulcers, gastrointestinal bleeding or the treatment of gastro-oesophageal reflux. Plasma samples were analysed using high-performance liquid chromatography, and the data were subjected to population pharmacokinetic analysis using nonlinear mixed-effects modelling. RESULTS A one-compartment model best described the plasma concentration profile, with an exponential structure for interindividual errors and a proportional structure for intra-individual error. After backward stepwise elimination, the final model showed a significant decrease in objective function value (-12.618; P < 0.001) compared with the weight-corrected base model. Final parameter estimates for the population were 32.1 l h(-1) for total clearance and 285 l for volume of distribution, both allometrically modelled for a 70 kg adult. Final estimates for absorption rate constant and bioavailability were 1.31 h(-1) and 27.5%, respectively. No significant relationship was found between age and weight-corrected ranitidine pharmacokinetic parameters in the final model, with the covariate for cardiac failure or surgery being shown to reduce clearance significantly by a factor of 0.46. CONCLUSIONS Currently, ranitidine dose recommendations are based on childrens weights. However, our findings suggest that a dosing scheme that takes into consideration both weight and cardiac failure/surgery would be more appropriate in order to avoid administration of higher or more frequent doses than necessary.

Quantitative analysis of methyl and propyl parabens in neonatal DBS using LC–MS/MS

AIM Excipients are used to overcome the chemical, physical and microbiological challenges posed by developing formulated medicines. Both methyl and propyl paraben are commonly used in pediatric liquid formulations. There is no data on systemic exposure to parabens in neonates. The European Study of Neonatal Exposure to Excipients project has investigated this. Results & methodology: DBS sampling was used to collect opportunistic blood samples. Parabens were extracted from the DBS and analyzed using a validated LC-MS/MS assay. DISCUSSION & CONCLUSION The above assay was applied to analyze neonatal DBS samples. The blood concentrations of parabens in neonates confirm systemic exposure to parabens following administration of routine medicines.

O-106 Populationpharmacokinetic Model Of The Antimicrobial Excipient Methyl Paraben Administered In Routine Clinical Practice To Neonates

Introduction Parabens are widely used as antimicrobial preservatives in medicines given to neonates. Some concerns have been raised about the potential of paraben toxicity. To date there have been no studies of the circulating concentrations of methyl paraben (MPB) in babies. This study aimed to describe the relationship between dose of MPB administered and circulating concentrations using a population pharmacokinetic model. Methods Neonates in 4 UK and 1 Estonian neonatal units who were prescribed paraben-containing medications were recruited with parental consent. Parabens were assayed in timed, dried blood spots using LCMSMS. The limit of quantification was 20ng/mL. Results 180 babies provided 841 samples of which 382 (45%) were below the limit of quantification. The mean (range) of observed blood MPB concentrations was 28.4 (10–874) ng/ml. The final kinetic model for MPB included first order absorption and two compartment disposition. Clearance was related to postnatal age (PNA). The model parameters are shown in the Table. Discussion Routine use of MPB as an excipient in medicinal formulations does not lead to markedly high circulating blood concentrations of MPB in neonates. We cannot exclude accumulation from these data. These findings will contribute to safety assessments and regulatory advice and may indicate that current levels of MPB in formulations are acceptable for young children. Abstract O-106 Table 1 Parameter Estimate % Relative Standard Error Clearance if PNA <21 days (L/hr) 0.57 9.57 Clearance if PNA ≥21 days (L/hr) 0.88 7.19 Central volume (L/1.6kg) 1.84 7.55 Peripheral Volume (L) 12.2 12.0 Residual (proportionate) Error (%) 44.5 4.7