Thiopurine metabolite levels in patients with atopic dermatitis and/or chronic hand/foot eczema treated with azathioprine

Background: Azathioprine is frequently used in severe eczema. It is converted in the liver into active metabolites, including 6-thioguanine nucleotide (6-TGN) and methylated 6-methylmercaptopurine (6-MMP). In the past, the therapeutic potential of azathioprine may have not been fully utilized. Recent investigations on inflammatory bowel disease have led to a better understanding of azathioprine metabolism and optimizing treatment. Objective: To investigate whether measuring thiopurine metabolites in circulation can improve the effectiveness and safety of azathioprine treatment in patients with atopic dermatitis and/or chronic hand/foot eczema. Methods: Azathioprine metabolite levels were measured in eczema patients during maintenance treatment (Part I) and dose escalation (Part II). Clinical effectiveness, hepatotoxicity, and bone marrow suppression were analyzed and TPMT genotype was assessed. Results: A wide variation in metabolite levels in all dose groups was observed. In Part I (32 patients), there were no significant differences in 6-TGN levels between clinical responders and non-responders (p = .806). No hepatoxicity or myelotoxicity was observed. In Part II, all 6-TGN and 6-MMP levels increased during dose escalation. Hypermethylation was observed in 2/8 patients. Conclusion: For individual eczema patients treated with azathioprine, routinely measuring 6-TGN and 6-MMP can be helpful in optimizing azathioprine dose, improving clinical effectiveness, and preventing side effects

Predicting therapy response to mycophenolic acid using UGT1A9 genotyping: towards personalized medicine in atopic dermatitis

Atopic dermatitis (AD) is a very common chronic inflammatory skin disease requiring long-term treatment. Mycophenolic acid (MPA) is used off-label in treatment of patients with severe AD failing Cyclosporin A (CsA) treatment, however clinical efficacy is observed in only half of the AD patients. In blood, MPA levels are known to have a large interindividual variability. Low MPA exposure and increased enzyme activity correlates with the presence of UGT1A9 polymorphisms. In this retrospective study, 65 adult AD patients treated with MPA were classified as responder or non-responder to MPA treatment. UGT1A9 polymorphisms were determined using PCR. A significantly higher number of UGT1A9 polymorphisms was found in the group that did not respond to MPA treatment. Of the patients that carried a UGT1A9 polymorphism, 85.7% were non-responsive to MPA treatment. This implies that non-responsiveness in AD patients is more likely to occur in carriers of a UGT1A9 polymorphism. In a binary logistic regression analysis the odds ratio (OR) was 8.65 (95% confidence interval: 0.93–80.17). Our results show that UGT1A9 polymorphisms can be used to identify patients with non-responsiveness to MPA. Patients with UGT1A9 polymorphisms might benefit from higher MPA dosage

Pharmacokinetics of morphine in encephalopathic neonates treated with therapeutic hypothermia

Objective Morphine is a commonly used drug in encephalopathic neonates treated with therapeutic hypothermia after perinatal asphyxia. Pharmacokinetics and optimal dosing of morphine in thi

Evaluation of a system-specific function to describe the pharmacokinetics of benzylpenicillin in term neonates undergoing moderate hypothermia

The pharmacokinetic (PK) properties of intravenous (i.v.) benzylpenicillin in term neonates undergoing moderate hypothermia after perinatal asphyxia were evaluated, as they have been unknown until now. A system-specific modeling approach was applied, in which our recently developed covariate model describing developmental and temperature-induced changes in amoxicillin clearance (CL) in the same patient study population was incorporated into a population PK model of benzylpenicillin with a priori birthweight (BW)-based allometric scaling. Pediatric population covariate models describing the developmental changes in drug elimination may constitute system-specific information and may therefore be incorporated into PK models of drugs cleared through the same pathway. The performance of this system-specific model was compared to that of a reference model. Furthermore, Monte-Carlo simulations were performed to evaluate the optimal dose. The systemspecific model performed as well as the reference model. Significant correlations were found between CL and postnatal age (PNA), gestational age (GA), body temperature (TEMP), urine output (UO; system-specific model), and multiorgan failure (reference model). For a typical patient with a GA of 40 weeks, BW of 3, 000 g, PNA of 2 days (TEMP, 33.5°C), and normal UO (2 ml/kg/h), benzylpenicillin CL was 0.48 liter/h (interindividual variability [IIV] of 49%) and the volume of distribution of the central compartment was 0.62 liter/kg (IIV of 53%) in the system-specific model. Based on simulations, we advise a benzylpenicillin i.v. dose regimen of 75, 000 IU/kg/day every 8 h (q8h), 150, 000 IU/kg/day q8h, and 200, 000 IU/kg/day q6h for patients with GAs of 36 to 37 weeks, 38 to 41 weeks, and ≥42 weeks, respectively. Thesystem-specific model may be used for other drugs cleared through the same pathway accelerating model development

Thermopharmacology of anticonvulsive treatment after perinatal asphyxia

Therapeutic hypothermia in the immediate postnatal period has been shown to be a successful strategy for neuroprotection in encephalopathic newborns in clinical trials. Due to the effect of hypothermia on physiological functions, such as heart rate and liver enzyme metabolic capacity, as well as effects on physico-chemical properties of the drugs, such as lipophilicity, pharmacokinetic and pharmacodynamic parameters may change. Depending on the mode of action and the route of inactivation/elimination, drugs are affected in a different way. We called the discipline that involves the investigation of drug effects as a function of body temperature, the effect of body temperature on drug disposition as well as the investigation of drug effects upon temperature homeostasis (or thermoregulation), “thermopharmacology”. The effect of therapeutic hypothermia on the clinical efficacy and safety of anticonvulsive treatment with phenobarbital, midazolam and lidocaine were studied in the prospective SHIVER study on the NICUs of the UMC Utrecht and the Isala Clinics, Zwolle. Clinicians are reluctant to prescribe (high) doses of phenobarbital in asphyxiated newborns because suppression of the aEEG background pattern has been noted to occur. We developed a pharmacokinetic-pharmacodynamic model using a multi-level Markov transition model to evaluate the safety and efficacy. Administration of phenobarbital under hypothermia seems to reduce the transition rate from Continuous Normal Voltage to Discontinuous Normal Voltage aEEG background level in hypothermic asphyxiated newborns, which may be attributed to additional neuroprotection. No (clinically relevant) thermopharmacological effect of moderate therapeutic hypothermia on phenobarbital pharmacokinetics could be identified. The observed responsiveness in our study population was 66%, which may be further increased if phenobarbital dosages in all newborns are increased to 40 mg/kg before switching to a second-line antiepileptic drug. Midazolam is notorious for its hypotensive adverse effects. Hypotension should be avoided, since it may cause neurological effects due to transient cerebral hypoperfusion, in particular during pressure-passive circulation in asphyxiated neonates. In our study population, 64% of the newborns experienced at least one hypotensive episode under midazolam treatment. With the developed pharmacokinetic-pharmacodynamic model we identified a relationship between the midazolam plasma concentration and decrease from baseline Mean Arterial Pressure. No effect of therapeutic hypothermia on drug exposure could be identified, but concomitant use of inotropes was identified as a significant covariate that decreased midazolam clearance by 33%. With a typical half-life of 5.2 hours for midazolam, neonatologists should be aware that the midazolam plasma concentration accumulates considerably over the first 12-24 hours. Add-on seizure control with midazolam was limited (23% seizure control). Lidocaine toxicity, mainly in the form of bradycardia and arrhythmias, is life-threatening and should be avoided. A reduced clearance of 24% was observed in the hypothermic newborn population. A response of 92% on epileptiform activity on the aEEG was observed under hypothermia for lidocaine add-on therapy in our population, which is better than the effect of other anti-epileptic drugs. No infants experienced cardiac arrhythmias. A lidocaine dosing regimen under hypothermia was developed in order to obtain comparable plasma concentrations as in normothermic patients accounting for the reduced clearance

Critical appraisal of evidence for anti-Xa monitoring and dosing of low-molecular-weight heparin in renal insufficiency

Introduction: Several guidelines advise to monitor therapeutic LMWH therapy with peak anti-Xa concentrations in renal insufficiency with subsequent dose adjustments. A better understanding of the clinical association between peak anti-Xa concentrations and clinical outcomes is mandatory, because misunderstanding this association could lead to erroneous, and potentially even harmful, LMWH dose adjustments. Areas covered: We reviewed the evidence of the widely applied therapeutic window for anti-Xa peak concentrations and report on the evidence for pharmacokinetic dose reduction in renal insufficiency, limitations of peak and trough anti-Xa concentration monitoring. Expert opinion: The added value of peak anti-Xa monitoring in patients with renal insufficiency, receiving a dose reduced for pharmacokinetic changes, is not supported by data. Enoxaparin and nadroparin should be adjusted to 50-65% and 75-85% of the original dose for patients with a creatinine clearance (CrCL) of Pharmacolog

Determination of pentachlorophenol in rabbit and human liver using liquid chromatography and gas chromatography with electron-capture detection

A method has been developed for the determination of ppb levels of pentachlorophenol (PCP) in liver by column liquid chromatography with on-line electron-capture detection (LC-ECD). The technique is compared with gas chromatography-ECD (GC-ECD) for the analysis of rabbit and human livers. Good results were generally obtained for LC-ECD down to the low-ppb range; however, in some cases problems were observed when the sample is not dissolved in the LC eluent. LC-ECD can adequately be used as a confirmation method for GC-ECD

Phenobarbital, Midazolam Pharmacokinetics, Effectiveness, and Drug-Drug Interaction in Asphyxiated Neonates Undergoing Therapeutic Hypothermia

Developmen