Hussain Mulla

Facilitating pharmacokinetic studies in children: a new use of dried blood spots.

Pharmacokinetic data are used to develop dosing regimens for medicines. The dose regimens of many drugs administered to children have historically been based on pharmacokinetic data generated in adults. The ‘adult’ dose was simply adjusted to the childs body weight or surface area. This practice is potentially unsafe and not acceptable to drug regulatory agencies. Obtaining pharmacokinetic data in children is beset with ethical issues and technical challenges as pharmacokinetic studies require repeated measurement of drug levels in blood. Dried blood spot (DBS) samples used in conjunction with population pharmacokinetic modelling techniques is one potential method for performing pharmacokinetic studies in children. In this article, we review the DBS technique for performing pharmacokinetic studies and highlight issues that still need to be addressed to establish DBS as a method for performing pharmacokinetic studies in children.

Toxic additives in medication for preterm infants

Background: Little is known about exposure of preterm infants to excipients during routine clinical care. Objective: To document excipient exposure in vulnerable preterm babies in a single centre, taking into account chronic lung disease (CLD) as a marker of illness severity. Design: Excipient exposure after treatment with eight oral liquid medications was determined by retrospectively analysing the drug charts of infants admitted to a neonatal unit. Setting: The Leicester Neonatal Service. Participants: 38 infants born between June 2005 and July 2006 who were less than 30 weeks’ gestation and 1500 g in weight at birth and managed in Leicester to discharge. Results: The 38 infants represented 53% of the eligible target group; 7/38 infants had CLD. During their in-patient stay, infants were exposed to over 20 excipients including ethanol and propylene glycol, chemicals associated with neurotoxicity. Infants with CLD were exposed to higher concentrations of these toxins. Infants were also exposed to high concentrations of sorbitol, with some infants being exposed to concentrations in excess of recommended guidelines for maximum exposure in adults. Conclusions: Preterm infants are commonly exposed to excipients, some of which are potentially toxic. Strategies aimed at reducing excipient load in preterm infants are urgently required

Pharmacokinetics of Midazolam in Neonates Undergoing Extracorporeal Membrane Oxygenation

Background Although the pharmacokinetics of midazolam in critically ill children has been described, there are no such reports in extracorporeal membrane oxygenation. Methods The pharmacokinetics of midazolam and 1-hydroxy midazolam after continuous infusion (50–250 &mgr;g · kg−1 · h−1) were determined in 20 neonates undergoing extracorporeal membrane oxygenation. Patients were randomized into two groups: group 1 (n = 10) received midazolam extracorporeally (into the circuit), and group 2 received drug via central or peripheral access. Blood samples for determination of plasma concentrations were taken at baseline, 2, 4, 6, 12, 18, and 24 h, then every 12 h. Population pharmacokinetic analysis and model building was conducted using WinNonMix (Pharsight Corporation, Mountain View, CA). The 1-hydroxy midazolam/midazolam metabolic ratio was determined as a surrogate marker of cytochrome P450 3A activity. Results The parameter estimates (n = 19) were based on a one-compartment model with time-dependent change in volume of distribution. Volume (mean ± standard error) expanded monoexponentially from the onset of extracorporeal membrane oxygenation to a maximum value, 0.8 l ± 0.5 and 4.1 ± 0.5 l/kg, respectively. Consequently, plasma half-life was substantially prolonged (median [range]) from onset to steady-state: 6.8 (2.2–39.8) and 33.3 (7.4–178) h, respectively. Total body clearance was determined as (mean ± standard error) 1.4 ± 0.15 ml · kg−1 · min−1. The median metabolic ratio was 0.17 (0.03–0.9). No significant differences were observed between the two groups with respect to parameter estimates. Simulations of plasma concentration profiles revealed excess levels at conventional doses. Conclusions These results reveal significantly increased volume of distribution and plasma half-life in neonates receiving extracorporeal membrane oxygenation. Altered kinetics may reflect sequestration of midazolam by components of the extracorporeal membrane oxygenation circuit.

Dexamethasone quantification in dried blood spot samples using LC–MS: The potential for application to neonatal pharmacokinetic studies

A high-performance liquid chromatography (LC-MS) method has been developed and validated for the determination of dexamethasone in dried blood spot (DBS) samples. For the preparation of DBS samples whole blood spiked with analyte was used to produce 30μl blood spots on specimen collection cards. An 8mm disc was cut from the DBS sample and extracted using a combination of methanol: water (70:30, v/v) containing the internal standard, triamcinolone acetonide. Extracts were centrifuged and chromatographic separation was achieved using a Zorbax Eclipse Plus C18 column using gradient elution with a mobile phase of acetonitrile and water with formic acid at a flow rate of 0.2ml/min. LC-MS detection was conducted with single ion monitoring using target ions at m/z 393.1 for dexamethasone and 435.1 for the internal standard. The developed method was linear within the tested calibration range of 15-800ng/ml. The overall extraction recovery of dexamethasone from DBS samples was 99.3% (94.3-105.7%). The accuracy (relative error) and precision (coefficient of variation) values were within the pre-defined limits of ≤15% at all concentrations. Factors with potential to affect drug quantification measurements such as blood haematocrit, the volume of blood applied onto the collection card and spotting device were investigated. Although a haematocrit related effect was apparent, the assay accuracy and precision values remained within the 15% variability limit with fluctuations in haematocrit of ±5%. Variations in the volume of blood spotted did not appear to affect the performance of the developed assay. Similar observations were made regarding the spotting device used. The methodology has been applied to determine levels of dexamethasone in DBS samples collected from premature neonates. The measured concentrations were successfully evaluated using a simple 1-compartment pharmacokinetic model. Requiring only a microvolume (30μl) blood sample for analysis, the developed assay is particularly suited to pharmacokinetic studies involving paediatric populations.

Venovenous Extracorporeal Membrane Oxygenation for Respiratory Failure in Inotrope Dependent Neonates

It is often stated that venovenous extracorporeal membrane oxygenation (VV ECMO) should not be used in inotrope dependent patients. It is our practice to use VV ECMO in most patients with respiratory failure even though many of these patients are receiving significant doses of inotropes. Our objective was to review the mode of ECMO in relation to precannulation doses of inotropes administered to neonates treated with ECMO for respiratory failure.Forty-three consecutive case notes were reviewed. Data were collected for basic demographic and ECMO parameters. Inotropic doses were converted to a single score for ease of comparison, with one point equivalent to 1 &mgr;g/kg/min dopamine.Forty-three neonates were studied; 37(86%) were treated with VV ECMO and 6 (14%) were treated with VA ECMO. Significant pre-ECMO inotropic support (score > 10) was present in 30 (70%) of the 43 cases. Of these patients, 26 were treated via VV ECMO with a survival rate of 84%, while 4 were treated with VA ECMO with a survival of 75%. Inotrope scores fell to nonsignificant levels (< 10) within 24 hours, regardless of ECMO mode. Mean arterial blood pressure remained above precannulation levels in both groups.VV ECMO allows safe treatment of neonatal respiratory failure in the presence of significant inotropic support. We recommend VV ECMO for neonatal respiratory failure in all cases except where double lumen cannulation is impossible or when septic shock is refractory to inotropic support (i.e., mean blood pressure < 35 mm Hg despite inotrope score of > 100).

Understanding Developmental Pharmacodynamics

Developmental pharmacodynamics is the study of age-related maturation of the structure and function of biologic systems and how this affects response to pharmacotherapy. This may manifest as a change in the potency, efficacy, or therapeutic range of a drug. The paucity of studies exploring developmental pharmacodynamics reflects the lack of suitable juvenile animal models and the ethical and practical constraints of conducting studies in children. However, where data from animal models are available, valuable insight has been gained into how response to therapy can change through the course of development. For example, animal neurodevelopmental models have revealed that temporal differences in the maturation of norepinephrine and serotonin neurotransmitter systems may explain the lack of efficacy of some anti-depressants in children. GABAA receptors that switch from an excitatory to inhibitory mode during early development help to explain paradoxical seizures experienced by infants after exposure to benzodiazepines. The increased sensitivity of neonates to morphine may be due to increased postnatal expression of the μ opioid receptor.An age dependency to the pharmacokinetic-pharmacodynamic relationship has also been found in some clinical studies. For example, immunosuppressive effects of ciclosporin (cyclosporine) revealed markedly enhanced sensitivity in infants compared with older children and adults. A study of sotalol in the treatment of children with supraventricular tachycardia showed that neonates exhibited a higher sensitivity towards QTc interval prolongation compared with older children. However, the data are limited and efforts to increase and establish data on developmental pharmacodynamics are necessary to achieve optimal drug therapy in children and to ensure long-term success of pediatric drug development. This requires a dual ‘bottom up’ (ontogeny knowledge driven) and ‘top down’ (pediatric pharmacokinetic-pharmacodynamic studies) approach.

High variability in the dosing of commonly used antibiotics revealed by a Europe-wide point prevalence study: implications for research and dissemination

BackgroundAntibiotic dosing in neonates varies between countries and centres, suggesting suboptimal exposures for some neonates. We aimed to describe variations and factors influencing the variability in the dosing of frequently used antibiotics in European NICUs to help define strategies for improvement.MethodsA sub-analysis of the European Study of Neonatal Exposure to Excipients point prevalence study was undertaken. Demographic data of neonates receiving any antibiotic on the study day within one of three two-week periods from January to June 2012, the dose, dosing interval and route of administration of each prescription were recorded. The British National Formulary for Children (BNFC) and Neofax were used as reference sources. Risk factors for deviations exceeding ±25% of the relevant BNFC dosage recommendation were identified by multivariate logistic regression analysis.ResultsIn 89 NICUs from 21 countries, 586 antibiotic prescriptions for 342 infants were reported. The twelve most frequently used antibiotics – gentamicin, penicillin G, ampicillin, vancomycin, amikacin, cefotaxime, ceftazidime, meropenem, amoxicillin, metronidazole, teicoplanin and flucloxacillin – covered 92% of systemic prescriptions. Glycopeptide class, GA <32 weeks, 5th minute Apgar score <5 and geographical region were associated with deviation from the BNFC dosage recommendation. While the doses of penicillins exceeded recommendations, antibiotics with safety concerns followed (gentamicin) or were dosed below (vancomycin) recommendations.ConclusionsThe current lack of compliance with existing dosing recommendations for neonates needs to be overcome through the conduct of well-designed clinical trials with a limited number of antibiotics to define pharmacokinetics/pharmacodynamics, efficacy and safety in this population and by efficient dissemination of the results.

Plasma concentrations of midazolam in neonates receiving extracorporeal membrane oxygenation

Drug disposition is affected during extracorporeal membrane oxygenation (ECMO). This study investigates the dose-concentration relationship of midazolam in neonates requiring ECMO during continuous infusion into the circuit (extracorporeally; n = 10) and intravenously (n = 10). Data on hourly doses and sedation scores were collected for 120 hours. Plasma concentrations were analyzed at times 0, 2, 4, 6, 12, 18, and 24, and every 12 hours thereafter. Both groups were clinically similar. Mean (standard deviation) dose for all patients was 250 (185) &mgr;g/kg/h, four times greater than previously reported. Doses administered in the first 24 hours were significantly greater extracorporeally [361 (300)] compared with intravenous [258 (190) &mgr;g/kg/h, p < 0.001]. Mean (standard deviation) plasma concentrations in all patients at 24, 48, and 72 hours were 1.4 (0.9), 1.8 (1.2), and 2.6 (1.8) &mgr;g/ml, respectively. Satisfactory sedation levels were achieved in all patients. Comparison of the actual observed with predicted (simulated) midazolam concentrations suggested significant attenuation of plasma levels during the first 24 hours of ECMO. However, at 48 hours, observed concentrations exceeded those predicted, suggesting accumulation. We conclude that in the first 24 hours of ECMO, because of an expanded circulating volume and sequestration by the circuit, significantly more midazolam is required to achieve adequate sedation. Subsequently, and because of circuit saturation, maintenance doses should be reduced.

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.

Extended-interval gentamicin: population pharmacokinetics in pediatric critical illness.

Objectives: Once-daily gentamicin therapy is becoming increasingly common in pediatric practice; however, little is known about pharmacokinetics in critical illness. Gentamicin exhibits concentration dependant killing; thus, peak serum concentrations at least eight times higher than minimum inhibition concentration of the target organism have been recommended. We wanted to derive pharmacokinetic parameters for gentamicin in critical illness and to evaluate whether a dose of 8 mg/kg provides an adequate peak serum concentration (>16 mg/L). Patients and Interventions: Population-based pharmacokinetic analyses were undertaken using therapeutic drug monitoring data collected prospectively in an intensive care unit over 6 months (n = 50 children). Monte Carlo simulations were used to estimate the probability of achieving 1) peak concentrations >16 mg/L; and 2) trough concentrations <2 mg/L at 24 and 36 hrs. Measurements and Main Results: The optimal pharmacokinetic model was of two-compartment disposition with zero order input and additive residual error. Weight was associated nonlinearly with clearance and linearly with volume, and age was a significant covariate for clearance. An 8-mg/kg dose provided near 100% probability of achieving adequate peak concentrations at all ages. However this probability decreased rapidly at doses <7 mg/kg with neonates being the most susceptible. Approximately 50% of nonpremature neonates within the first week of life, 25% of infants, and 10% of children are likely to need a dose interval >24 hrs. Conclusions: A gentamicin dose of 8 mg/kg is highly likely to achieve peak concentrations >16 mg/L in critically ill children. A considerable proportion will require dose intervals >24 hrs; thus, therapeutic drug monitoring is essential.