Marcel P. H. van den Broek

Effects of Hypothermia on Pharmacokinetics and Pharmacodynamics

Examples of clinical applications of therapeutic hypothermia in modern clinical medicine include traumatic cardiac arrest, ischaemic stroke and, more recently, acute perinatal asphyxia in neonates. The exact mechanism of (neuro)protection by hypothermia is unknown. Since most enzymatic processes exhibit temperature dependency, it can be expected that therapeutic hypothermia may cause alterations in both pharmacokinetic and pharmacodynamic parameters, which could result in an increased risk of drug toxicity or therapy failure. Generalizable knowledge about the effect of therapeutic hypothermia on pharmacokinetics and pharmacodynamics could lead to more appropriate dosing and thereby prediction of clinical effects. This article reviews the evidence on the influence of therapeutic hypothermia on individual pharmacokinetic and pharmacodynamic parameters. A literature search was conducted within the PubMed, Embase and Cochrane databases from January 1965 to September 2008, comparing pharmacokinetic and/or pharmacodynamic parameters in hypothermia and normothermia regarding preclinical (animal) and clinical (human) studies. During hypothermia, pharmacokinetic parameters alter, resulting in drug and metabolite accumulation in the plasma for the majority of drugs. Impaired clearance is the most striking effect. Based on impaired clearance, dosages should be decreased considerably, especially for drugs with a low therapeutic index. Hypothetically, high-clearance compounds are affected more than low-clearance compounds because of the additional effect of impaired hepatic blood flow. The volume of distribution also changes, which may lead to therapy failure when it increases and could lead to toxicity when it decreases. The pH-partitioning hypothesis could contribute to the changes in the volumes of distribution for weak bases and acids, depending on their acid dissociation constants and acid-base status. Pharmacodynamic parameters may also alter, depending on the hypothermic regimen, drug target location, pharmacological mechanism and metabolic pathway of inactivation. The pharmacological response changes when target sensitivity alters. Rewarming patients to normothermia can also result in toxicity or therapy failure. The integrated effect of hypothermia on pharmacokinetic and pharmacodynamic properties of individual drugs is unclear. Therefore, therapeutic drug monitoring is currently considered essential for drugs with a low therapeutic index, drugs with active metabolites, high-clearance compounds and drugs that are inactivated by enzymes at the site of effect. Because most of the studies (74%) included in this review contain preclinical data, clinical pharmacokinetic/pharmacodynamic studies are essential for the development of substantiated dose regimens to avoid toxicity and therapy failure in patients treated with hypothermia.

Allogeneic Mesenchymal Stem Cells Stimulate Cartilage Regeneration and Are Safe for Single‐Stage Cartilage Repair in Humans upon Mixture with Recycled Autologous Chondrons

Traditionally, mesenchymal stem cells (MSCs) isolated from adult bone marrow were described as being capable of differentiating to various lineages including cartilage. Despite increasing interest in these MSCs, concerns regarding their safety, in vivo behavior and clinical effectiveness have restrained their clinical application. We hypothesized that MSCs have trophic effects that stimulate recycled chondrons (chondrocytes with their native pericellular matrix) to regenerate cartilage. Searching for a proof of principle, this phase I (first‐in‐man) clinical trial applied allogeneic MSCs mixed with either 10% or 20% recycled autologous cartilage‐derived cells (chondrons) for treatment of cartilage defects in the knee in symptomatic cartilage defect patients. This unique first in man series demonstrated no treatment‐related adverse events up to one year postoperatively. At 12 months, all patients showed statistically significant improvement in clinical outcome compared to baseline. Magnetic resonance imaging and second‐look arthroscopies showed completely filled defects with regenerative cartilage tissue. Histological analysis on biopsies of the grafts indicated hyaline‐like regeneration with a high concentration of proteoglycans and type II collagen. Short tandem repeat analysis showed the regenerative tissue only contained patient‐own DNA. These findings support the novel insight that the use of allogeneic MSCs is safe and opens opportunities for other applications. Stem cell‐induced paracrine mechanisms may play an important role in the chondrogenesis and successful tissue regeneration found. Stem Cells 2017;35:256–264

Lidocaine (Lignocaine) Dosing Regimen Based upon a Population Pharmacokinetic Model for Preterm and Term Neonates with Seizures

AbstractBackground and Objective: The application of lidocaine (lignocaine) as an anticonvulsant in neonates originated more than 40 years ago in Scandinavia. Lidocaine has been shown to be an effective anticonvulsant for the treatment of neonatal seizures that persist in spite of first-line anticonvulsant therapy. However, lidocaine toxicity, mainly in the form of cardiac arrhythmias, can be life threatening. Therapeutic drug monitoring can be useful to prevent toxicity. In a previous study, a dosing regimen was developed for term neonates, but it was not evaluated for preterm neonates. Extrapolation of the previously developed dosing regimen to premature neonates without accounting for differences in pharmacokinetics because of immaturity of phase I metabolism and body fat/water ratio may result in serious toxicity or therapy failure. The objective of this study was to develop an optimized dosing regimen for lidocaine in preterm as well as term neonates, using population pharmacokinetic modelling and simulation. Methods: The requirements for this dosing regimen were simplicity of implementation, equal initial doses for all weight categories and avoidance of plasma concentrations >9mg/L. After lidocaine administration, blood samples were collected from an arterial line from a total of 46 preterm and term neonates with convulsion, within 10 days after birth. Lidocaine concentrations were measured in plasma using a fluorescence polarization immunoassay. Population pharmacokinetic modelling started with assessment of two important aspects of paediatric pharmacokinetics: relation to body size and the effects of maturation. Results: In the studied neonatal population (term and preterm neonates with gestational ages up to 10 days), gestational age and bodyweight were closely related. Therefore, the effects of allometry and maturation on lidocaine pharmacokinetics could not be described independently and were described by a combined power estimate of bodyweight on clearance and volume of distribution. Based on this pharmacokinetic model, a dosing strategy for lidocaine for neonatal seizure control was developed, which allows rapid and safe administration of lidocaine in this population. When prospective validation confirms our model, routinely performed therapeutic drug monitoring should no longer be necessary and would only be advised in cases of (suspected) clinical symptoms of over- or underdosing. Conclusion: A lidocaine dosing regimen for seizure control in preterm and term neonates has been developed using population pharmacokinetic modelling and simulation. Allometry and maturation exponents were combined into one exponent for each pharmacokinetic parameter and could not be described independently. Based on this model, this regimen allows rapid and safe administration of lidocaine in this population.

Pharmacokinetics and pharmacodynamics of medication in asphyxiated newborns during controlled hypothermia. The PharmaCool multicenter study

BackgroundIn the Netherlands, perinatal asphyxia (severe perinatal oxygen shortage) necessitating newborn resuscitation occurs in at least 200 of the 180–185.000 newly born infants per year. International randomized controlled trials have demonstrated an improved neurological outcome with therapeutic hypothermia. During hypothermia neonates receive sedative, analgesic, anti-epileptic and antibiotic drugs. So far little information is available how the pharmacokinetics (PK) and pharmacodynamics (PD) of these drugs are influenced by post resuscitation multi organ failure and the metabolic effects of the cooling treatment itself. As a result, evidence based dosing guidelines are lacking. This multicenter observational cohort study was designed to answer the question how hypothermia influences the distribution, metabolism and elimination of commonly used drugs in neonatal intensive care.Methods/DesignMulticenter cohort study. All term neonates treated with hypothermia for Hypoxic Ischemic Encephalopathy (HIE) resulting from perinatal asphyxia in all ten Dutch Neonatal Intensive Care Units (NICUs) will be eligible for this study. During hypothermia and rewarming blood samples will be taken from indwelling catheters to investigate blood concentrations of several antibiotics, analgesics, sedatives and anti-epileptic drugs. For each individual drug the population PK will be characterized using Nonlinear Mixed Effects Modelling (NONMEM). It will be investigated how clearance and volume of distribution are influenced by hypothermia also taking maturation of neonate into account. Similarly, integrated PK-PD models will be developed relating the time course of drug concentration to pharmacodynamic parameters such as successful seizure treatment; pain assessment and infection clearance.DiscussionOn basis of the derived population PK-PD models dosing guidelines will be developed for the application of drugs during neonatal hypothermia treatment. The results of this study will lead to an evidence based drug treatment of hypothermic neonatal patients. Results will be published in a national web based evidence based paediatric formulary, peer reviewed journals and international paediatric drug references.Trial registrationNTR2529.

Clinical Management of Seizures in Newborns

Neonatal seizures can be classified as tonic, clonic, myoclonic, and subtle. A clinical diagnosis is not easy as seizures are usually subtle in neonates. In the majority of newborn infants seizures are subclinical. On the other hand, not all abnormal movements identified by clinicians as clinical seizures are accompanied by electroencephalographic seizure discharges in the EEG. Precise incidence is difficult to delineate and depends on study population and criteria used for diagnosis of seizures. Controversy exists as to whether neonatal seizures themselves cause damage to the developing brain, or if the damage is primarily due to the underlying cause of the seizures. As a result of this controversy there is ongoing discussion whether all seizures (both clinical and subclinical) should be treated. In addition, when (sub)clinical seizures are treated, there is no consensus about the most appropriate treatment for neonatal seizures and how to assess the efficacy of treatment.Current therapeutic options to treat neonatal seizures (i.e. primarily first-generation antiepileptic drugs [AEDs]) are relatively ineffective. In practice, phenobarbital still remains the drug of first choice for EEG confirmed or suspected seizures. Benzodiazepines are also used in (phenobarbital) refractory cases. Several (small) studies indicate that lidocaine is an effective drug for refractory seizures as second- or third-line treatment. Although data are scarce, some AEDs with a wide acceptance in adult and pediatric neurology practice are being used to treat neonatal seizures (i.e. second-generation AEDs). These drugs are chemically different from all first-generation AEDs and they have an effect on other pathways so they provide new pharmacological targets for controlling seizures in newborns. Levetiracetam, topiramate, felbamate, bumetanide, lamotrigine and vigabatrin are examples of these second-generation AEDs.There is an urgent need for prospective, randomized, controlled trials to assess the efficacy and safety of these second-generation AEDs in neonates.The aim of this review is to provide an overview of the current knowledge of diagnosis, the effect on brain injury, and the treatment of neonatal seizures.

Anticonvulsant treatment of asphyxiated newborns under hypothermia with lidocaine: efficacy, safety and dosing

Background Lidocaine is an antiarrythmicum used as an anticonvulsant for neonatal seizures, also during therpeutic hypothermia following (perinatal) asphyxia. Hypothermia may affect the efficacy, safety and dosing of lidocaine in these patients. Objective To study the efficacy and safety of lidocaine in newborns with perinatal asphyxia during moderate hypothermia, and to develop an effective and safe dosing regimen. Methods Hypothermic newborns with perinatal asphyxia and lidocaine for seizure control were included. Efficacy was studied using continuous amplitude-integrated electroencephalography. Safety was assessed using continuous cardiac monitoring. An optimal dosing regimen was developed with simulations using data from a pharmacokinetic model. Plasma samples were collected during hypothermia on consecutive mornings. Results A total of 22 hypothermic and 26 historical normothermic asphyxiated newborns with lidocaine were included. A response of 91% on epileptiform activity on the amplitude-integrated EEG was observed for lidocaine add-on therapy. No relationship between lidocaine or MEGX plasma concentrations and heart frequency could be identified. None of the newborns experienced cardiac arrythmias. Hypothermia reduced lidocaine clearance by 24% compared with normothermia. A novel dosing regimen was developed an initial bolus loading dose of 2 mg/kg, for patients with body weight 2.0–2.5 kg followed by consecutive continuous infusions of 6 mg/kg/h (for 3.5 h), 3 mg/kg/h (for 12 h), 1.5 mg/kg/h (for 12 h), or for patients with bodyweights 2.5–4.5 kg 7 mg/kg/h (for 3.5 h), 3.5 mg/kg/h (for 12 h), 1.75 mg/kg/h (for 12 h), before stopping. Conclusions Lidocaine can be assumed to be an effective antiepileptic drug during hypothermia in asphyxiated neonates.

Pretransplantation pharmacokinetic curves of tacrolimus in HIV-infected patients on ritonavir-containing cART: a pilot study.

Background Ritonavir is an extremely strong inhibitor of P450 cytochrome 3A, which is the main metabolizing enzyme of tacrolimus. Subsequently, the pharmacokinetics of tacrolimus are affected to a large extend by the coadministration of ritonavir in HIV-infected transplant recipients. Therefore, to prevent overexposure directly posttransplantation in HIV-infected patients on ritonavir-containing cART, the predictive value of a pretransplantation pharmacokinetic curve of tacrolimus was explored. Methods A pretransplantation pharmacokinetic model of tacrolimus in these patients was developed, and a posttransplantation dosing advice was established for each individual patient. The pharmacokinetic population parameters were compared with HIV-negative patients, and predictive value of the pretransplantation curves was assessed in patients after the transplantation procedure. Results No significant difference was found between the model-predicted and actual posttransplantation 24 h-tacrolimus levels (14.6 vs. 17.8 ng/mL, P=0.19). As the simulated pharmacokinetic curves lacked an absorption peak every 12 h, the mean 12 h-AUC was approximately 40 % lower compared with AUC’s reported in HIV-negative recipients, when similar trough levels were targeted. Conclusion In conclusion, pretransplantation curves of tacrolimus seem a promising tool to prevent overexposure directly posttransplantation in patients on ritonavir-containing cART and raising trough levels to achieve an exposure equivalent to HIV-negative recipients is suggested.

Lidocaine response rate in aEEG-confirmed neonatal seizures: Retrospective study of 413 full-term and preterm infants.

To investigate the seizure response rate to lidocaine in a large cohort of infants who received lidocaine as second‐ or third‐line antiepileptic drug (AED) for neonatal seizures.

Quantification of active infliximab in human serum with liquid chromatography–tandem mass spectrometry using a tumor necrosis factor alpha -based pre-analytical sample purification and a stable isotopic labeled infliximab bio-similar as internal standard : A target-based, sensitive and cost-effective method

The therapeutic monoclonal antibody Infliximab (IFX) is a widely used drug for the treatment of several inflammatory autoimmune diseases. However, approximately 10% of patients develop anti-infliximab antibodies (ATIs) rendering the treatment ineffective. Early detection of underexposure to unbound IFX would result in a timely switch of therapy which could aid in the treatment of this disease. Streptavidin coated 96 well plates were used to capture biotinylated-tumor necrosis factor -alpha (b-TNF-α), which in turn was used to selectively extract the active form of IFX in human serum. After elution, IFX was digested using trypsin and one signature peptide was selected for subsequent analysis on liquid chromatography-tandem mass spectrometry (LC-MS/MS). The internal standard used was a stable isotopic labeled IFX bio-similar. The assay was successfully validated according to European Medicines Agency (EMA) guidelines and was found to be linear in a range of 0.5-20μg/mL (r(2)=0.994). Lower limit of quantification for the assay (<20% CV) was 0.5μg/mL, requiring only 2μL of sample. Cross-validation against enzyme-linked immunosorbent assay (ELISA) resulted in a high correlation between methods (r(2)=0.95 with a ρc=0.83) and the accuracy was in line with previously published results. In conclusion, a sensitive, robust and cost-effective method was developed for the bio-analysis of IFX with LC-MS/MS by means of a target-based pre-analytical sample purification. Moreover, low volume and costs of consumables per sample promote its feasibility in (pre)clinical studies and in therapeutic drug monitoring. This method should be considered as first choice due to its accuracy and multiple degree of selectivity.

Anticonvulsant effectiveness and hemodynamic safety of midazolam in full-term infants treated with hypothermia

Background: Midazolam is used as an anticonvulsant in neonatology, including newborns with perinatal asphyxia treated with hypothermia. Hypothermia may affect the safety and effectiveness of midazolam in these patients. Objectives: The objective was to evaluate the anticonvulsant effectiveness and hemodynamic safety of midazolam in hypothermic newborns and to provide dosing guidance. Methods: Hypothermic newborns with perinatal asphyxia and treated with midazolam were included. Effectiveness was studied using continuous amplitude-integrated electroencephalography. Hemodynamic safety was assessed using pharmacokinetic-pharmacodynamic modeling with plasma samples and blood pressure recordings (mean arterial blood pressure) under hypothermia. Results: No effect of therapeutic hypothermia on pharmacokinetics could be identified. Add-on seizure control with midazolam was limited (23% seizure control). An inverse relationship between the midazolam plasma concentration and mean arterial blood pressure could be identified. At least one hypotensive episode was experienced in 64%. The concomitant use of inotropes decreased midazolam clearance by 33%. Conclusions: Under therapeutic hypothermia, midazolam has limited add-on clinical anticonvulsant effectiveness after phenobarbital administration. Due to occurrence of hypotension requiring inotropic support, midazolam is less suitable as a second-line anticonvulsant drug under hypothermia.