Although children cannot be considered small adults due to nonlinear processes underlying the pharmacokinetics of drugs, pediatric doses are typically still expressed per kilogram. We use a... Show moreAlthough children cannot be considered small adults due to nonlinear processes underlying the pharmacokinetics of drugs, pediatric doses are typically still expressed per kilogram. We use a physiologically based pharmacokinetic (PBPK) workflow to assess the accuracy of linear scaling of plasma clearance (CLp) for hypothetical drugs with ranges of realistic parameter values in pediatric patients of different ages. The results are compared with 0.75 fixed allometric scaling (AS 0.75). Linear CLp scaling is accurate down to the age of 1 month for drugs undergoing glomerular filtration, except when these drugs are highly bound to alpha-1-acid glycoprotein (AGP). For hepatically cleared drugs, linear scaling is reasonably accurate down the age of 2 years, except for AGP-bound drugs with a low extraction ratio and mature isoenzymes. In neonates, linear scaling outperforms AS 0.75 for human serum albumin (HSA) and AGP-bound drugs excreted through glomerular filtration. These results suggest that pediatric patients can, in many cases, be treated as small adults. Show less
Hoogd, S. de; Valkenburg, A.J.; Dongen, E.P.A. van; Daeter, E.J.; Rosmalen, J. van; Dahan, A.; ... ; Knibbe, C.A.J. 2019
Earlier reports of increased pain sensitivity 1 year after the use of remifentanil could not be confirmed in this randomised study using Quantitative Sensory Testing. This indicates that... Show moreEarlier reports of increased pain sensitivity 1 year after the use of remifentanil could not be confirmed in this randomised study using Quantitative Sensory Testing. This indicates that remifentanil plays a minor role in the development of chronic thoracic pain. Still, the relatively high incidence of chronic thoracic pain and its accompanying impact on quality of life remain challenging problems.\nBoth warm and cold detection, and pain thresholds, were not significantly different between the remifentanil and fentanyl groups 3 days and 12 months after surgery (P > 0.05). No significant predictors for altered pain sensitivity were identified.\nThe study was registered at EudraCT (ref: 2013-000201-23) and ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT02031016).\nThe clinical relevance of the suggested hyperalgesic effects of remifentanil is still unclear, especially in the long term.\nThe current study evaluated the impact of remifentanil on thermal thresholds 3 days and 12 months after surgery, measured with Quantitative Sensory Testing.\nA single-blind, randomised controlled trial.\nA tertiary care teaching hospital in The Netherlands, from 2014 to 2016.\nA total of 126 patients aged between 18 and 85 years, undergoing cardiothoracic surgery via sternotomy (coronary artery bypass grafts and/or valve replacement) were included. Exclusion criteria were BMI above 35 kg m, history of cardiac surgery, chronic pain conditions, neurological conditions, allergy to opioids or paracetamol, language barrier and pregnancy.\nPatients were allocated randomly to receive intra-operatively either a continuous remifentanil infusion or intermittent intra-operative fentanyl as needed in addition to standardised anaesthesia with propofol and intermittent intravenous fentanyl at predetermined time points.\nWarm and cold detection and pain thresholds 3 days and 12 months after surgery. In addition the use of remifentanil, presence of postoperative chronic pain, age, opioid consumption and pre-operative quality of life were tested as a predictor for altered pain sensitivity 12 months after surgery.\nCONCLUSION\nRESULTS\nTRIAL REGISTRATION\nBACKGROUND\nOBJECTIVE\nDESIGN\nSETTING\nPATIENTS\nINTERVENTIONS\nMAIN OUTCOME MEASURES Show less
Blussé van Oud-Alblas, H.J.; Brill, M.J.E.; Peeters, M.Y.M.; Tibboel, D.; Danhof, M.; Knibbe, C.A.J. 2019
Background: In adolescents limited data are available on the pharmacokinetics (PK) and pharmacodynamics (PD) of propofol. In this study we derived a PK-PD model for propofol in adolescents... Show moreBackground: In adolescents limited data are available on the pharmacokinetics (PK) and pharmacodynamics (PD) of propofol. In this study we derived a PK-PD model for propofol in adolescents undergoing idiopathic scoliosis surgery with an intraoperative wake-up test with reinduction of anesthesia using both Bispectral Index (BIS) and composite A-line ARX index (cAAI) as endpoints.Methods: Fourteen adolescents (9.8-20.1 years) were evaluated during standardized propofol-remifentanil anesthesia for idiopathic scoliosis surgery with an intraoperative wake-up test with reinduction of anesthesia. BIS and cAAI were continuously measured and blood samples collected. A propofol PKPD model was developed using NONMEM.Results: The time courses of propofol concentrations, BIS and cAAI values during anesthesia, intra-operative wakeup and reduction of anesthesia were best described by a two-compartment PK model linked to an inhibitory sigmoidal Emax PD model. For the sigmoidal Emax model, the propofol concentration at half maximum effect (EC50) was 3.51 and 2.14 mg/L and Hill coefficient 1.43 and 6.85 for BIS and cAAI, respectively. The delay in PD effect in relation to plasma concentration was best described by a two compartment effect-site model with a ke(o) of 0.102 min(-1), ke(12) of 0. 121 min(-1) and ke(21) of 0.172 min(-1).Conclusions: A population PKPD model for propofol in adolescents was developed that successfully described the time course of propofol concentration, BIS and cAAI in individuals upon undergoing scoliosis surgery with intraoperative wake-up test and reinduction of anesthesia. Large differences were demonstrated between both monitors. This may imply that BIS and cAAI measure fundamentally different endpoints in the brain. Show less
ObjectivesThe rising pandemic of obesity means an increasing number of obese patients who require antimicrobial therapy for serious infections. Micafungin is an echinocandin drug frequently used as... Show moreObjectivesThe rising pandemic of obesity means an increasing number of obese patients who require antimicrobial therapy for serious infections. Micafungin is an echinocandin drug frequently used as therapy or prophylaxis for fungal infections, predominantly with Candida species. In order to maximize the efficacy of micafungin in obese patients, the dose that corresponds to optimal exposure for each obese individual needs to be identified.MethodsWe performed a prospective study in 16 obese and 8 normal-weight healthy subjects with a weight ranging from 61.5–184 kg (ClinicalTrials.gov Identifier: NCT03102658). A population pharmacokinetic model was developed and used to simulate several dosing regimens to evaluate the PTA for relevant MICs to define the optimal dose using the pharmacokinetic/pharmacodynamic target of an AUC/MIC ratio above 5000.ResultsTotal body weight was found to be most predictive for CL and V. Simulations showed that a 100 mg dose results in a PTA of >90% in patients weighing ≤125 kg infected with a Candida species having an MIC of 0.016 mg/L. The maintenance dose should be increased to 200 mg in patients >125 kg infected with a Candida species with an MIC of 0.016 mg/L. For an MIC of 0.032 mg/L, a 300 mg maintenance dose is recommended above 125 kg weight. Furthermore, we demonstrate that patients can benefit from a loading dose (i.e. twice the maintenance dose).ConclusionsWe present easy-to-use dose recommendations for obese patients, based on both weight and target MIC, that result in adequate exposure in patients with body weight up to 190 kg. Show less
Groen, B.D. van; Vaes, W.H.; Park, B.K.; Krekels, E.H.J.; Duijn, E. van; Körgvee, L.T.; ... ; Turner, M.A. 2019
Aims Drug disposition in children may vary from adults due to age-related variation in drug metabolism. Microdose studies present an innovation to study pharmacokinetics (PK) in paediatrics;... Show moreAims Drug disposition in children may vary from adults due to age-related variation in drug metabolism. Microdose studies present an innovation to study pharmacokinetics (PK) in paediatrics; however, they should be used only when the PK is dose linear. We aimed to assess dose linearity of a [C-14]midazolam microdose, by comparing the PK of an intravenous (IV) microtracer (a microdose given simultaneously with a therapeutic midazolam dose), with the PK of a single isolated microdose. Methods Preterm to 2-year-old infants admitted to the intensive care unit received [C-14]midazolam IV as a microtracer or microdose, followed by dense blood sampling up to 36 hours. Plasma concentrations of [C-14]midazolam and [C-14]1-hydroxy-midazolam were determined by accelerator mass spectrometry. Noncompartmental PK analysis was performed and a population PK model was developed. Results Of 15 infants (median gestational age 39.4 [range 23.9-41.4] weeks, postnatal age 11.4 [0.6-49.1] weeks), 6 received a microtracer and 9 a microdose of [C-14]midazolam (111 Bq kg(-1); 37.6 ng kg(-1)). In a 2-compartment PK model, bodyweight was the most significant covariate for volume of distribution. There was no statistically significant difference in any PK parameter between the microdose and microtracer, nor in the area under curve ratio [C-14]1-OH-midazolam/[C-14]midazolam, showing the PK of midazolam to be linear within the range of the therapeutic and microdoses. Conclusion Our data support the dose linearity of the PK of an IV [C-14]midazolam microdose in children. Hence, a [C-14]midazolam microdosing approach may be used as an alternative to a therapeutic dose of midazolam to study developmental changes in hepatic CYP3A activity in young children. Show less
Groen, B.D. van; Vaes, W.H.; Park, B.K.; Krekels, E.H.J.; Duijn, E. van; Körgvee, L.T.; ... ; Turner, M.A. 2019
Aims Drug disposition in children may vary from adults due to age-related variation in drug metabolism. Microdose studies present an innovation to study pharmacokinetics (PK) in paediatrics;... Show moreAims Drug disposition in children may vary from adults due to age-related variation in drug metabolism. Microdose studies present an innovation to study pharmacokinetics (PK) in paediatrics; however, they should be used only when the PK is dose linear. We aimed to assess dose linearity of a [C-14]midazolam microdose, by comparing the PK of an intravenous (IV) microtracer (a microdose given simultaneously with a therapeutic midazolam dose), with the PK of a single isolated microdose. Methods Preterm to 2-year-old infants admitted to the intensive care unit received [C-14]midazolam IV as a microtracer or microdose, followed by dense blood sampling up to 36 hours. Plasma concentrations of [C-14]midazolam and [C-14]1-hydroxy-midazolam were determined by accelerator mass spectrometry. Noncompartmental PK analysis was performed and a population PK model was developed. Results Of 15 infants (median gestational age 39.4 [range 23.9-41.4] weeks, postnatal age 11.4 [0.6-49.1] weeks), 6 received a microtracer and 9 a microdose of [C-14]midazolam (111 Bq kg(-1); 37.6 ng kg(-1)). In a 2-compartment PK model, bodyweight was the most significant covariate for volume of distribution. There was no statistically significant difference in any PK parameter between the microdose and microtracer, nor in the area under curve ratio [C-14]1-OH-midazolam/[C-14]midazolam, showing the PK of midazolam to be linear within the range of the therapeutic and microdoses. Conclusion Our data support the dose linearity of the PK of an IV [C-14]midazolam microdose in children. Hence, a [C-14]midazolam microdosing approach may be used as an alternative to a therapeutic dose of midazolam to study developmental changes in hepatic CYP3A activity in young children. Show less
Groen, B.D. van; Vaes, W.H.; Park, B.K.; Krekels, E.H.J.; Duijn, E. van; Körgvee, L.T.; ... ; Turner, M.A. 2019
Aims Drug disposition in children may vary from adults due to age-related variation in drug metabolism. Microdose studies present an innovation to study pharmacokinetics (PK) in paediatrics;... Show moreAims Drug disposition in children may vary from adults due to age-related variation in drug metabolism. Microdose studies present an innovation to study pharmacokinetics (PK) in paediatrics; however, they should be used only when the PK is dose linear. We aimed to assess dose linearity of a [C-14]midazolam microdose, by comparing the PK of an intravenous (IV) microtracer (a microdose given simultaneously with a therapeutic midazolam dose), with the PK of a single isolated microdose. Methods Preterm to 2-year-old infants admitted to the intensive care unit received [C-14]midazolam IV as a microtracer or microdose, followed by dense blood sampling up to 36 hours. Plasma concentrations of [C-14]midazolam and [C-14]1-hydroxy-midazolam were determined by accelerator mass spectrometry. Noncompartmental PK analysis was performed and a population PK model was developed. Results Of 15 infants (median gestational age 39.4 [range 23.9-41.4] weeks, postnatal age 11.4 [0.6-49.1] weeks), 6 received a microtracer and 9 a microdose of [C-14]midazolam (111 Bq kg(-1); 37.6 ng kg(-1)). In a 2-compartment PK model, bodyweight was the most significant covariate for volume of distribution. There was no statistically significant difference in any PK parameter between the microdose and microtracer, nor in the area under curve ratio [C-14]1-OH-midazolam/[C-14]midazolam, showing the PK of midazolam to be linear within the range of the therapeutic and microdoses. Conclusion Our data support the dose linearity of the PK of an IV [C-14]midazolam microdose in children. Hence, a [C-14]midazolam microdosing approach may be used as an alternative to a therapeutic dose of midazolam to study developmental changes in hepatic CYP3A activity in young children. Show less
Smit, C.; Hoogd, S. de; Bruggemann, R.J.M.; Knibbe, C.A.J. 2018
BackgroundObesity and its related complications are increasing health issues. Since generally only minor weight loss is obtained with lifestyle intervention, additional pharmacological therapies... Show moreBackgroundObesity and its related complications are increasing health issues. Since generally only minor weight loss is obtained with lifestyle intervention, additional pharmacological therapies such as metformin are often used.ObjectiveWe conducted a systematic review to provide an overview of the efficacy of ≥ 6 months of metformin treatment in children and adults with respect to weight, insulin resistance, and progression toward type 2 diabetes mellitus (T2DM).MethodsIn September 2018, we searched PubMed, Embase, and the Cochrane Library for studies published in English using the keywords metformin, obesity/overweight, and weight loss. Prospective studies reporting weight/body mass index (BMI) as a primary or secondary outcome in patients with overweight/obesity with ≥ 6 months’ metformin treatment were included. Included subjects were children and adults with overweight/obesity who received ≥ 6 months of metformin and/or lifestyle intervention, and/or placebo and/or lifestyle intervention, and/or standard care. Studies were independently screened by two reviewers. Data were extracted by one and verified by the other reviewer, and both reviewers assessed the risk of bias using the Cochrane risk-of-bias tool.ResultsOur review includes 15 pediatric and 14 adult studies. In children, after 6 months, more than half the studies reported a greater reduction in BMI with metformin versus controls. Only six studies had an intervention of > 6 months, and these studies found no further improvement in BMI in the metformin users, though their BMI was lower than that of controls. Three studies showed a significant improvement in insulin sensitivity in the metformin versus the control group. Adults using metformin experienced and maintained small decreases in weight irrespective of duration of intervention. In 11 of 14 studies, a greater reduction in weight/BMI was observed with metformin than with placebo. Progression toward T2DM was significantly reduced in adults using metformin, ranging from 7 to 31%. The safety and tolerability of metformin, withdrawal of participants, and comparison with other drugs were not taken into account.ConclusionsThe effects of metformin on weight/BMI vary, with smaller reductions in children than in adults. This could be because of differences in adherence, daily dosage, and insulin status. Metformin significantly reduced the progression toward T2DM in adults. Therefore, metformin should be considered as a treatment for obesity and its related complications. Show less
