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To evaluate the effect of extracorporeal membrane oxygenation (ECMO) support on pharmacokinetics of oseltamivir and oseltamivir carboxylate (OC) in children. Steady state 0-12 hour pharmacokinetic sampling was performed in new influenza A (H1N1) infected children treated with oseltamivir while on ECMO support. Cmax, Cmin and AUC(0-12 h) were calculated. The age-specific oseltamivir dosage was doubled to counter expected decreased plasma drug concentrations due to increased volume of distribution on ECMO support. Three patients were enrolled aged 15, 6 and 14 years in this pharmacokinetic case series. For two children the OC plasma concentrations were higher than those found in children and adults not on ECMO. These increased plasma concentrations related to the increased oseltamivir dosage and decreased kidney function. In one patient suboptimal plasma concentrations coincided with a decreased gastric motility. Oseltamivir pharmacokinetics do not appear to be significantly influenced by ECMO support. Caution is required in case of nasogastric administration and decreased gastric motility. Due to the limited number of (paediatric) patients available further multicenter studies are warranted.

Uprifosbuvir is a uridine nucleoside monophosphate prodrug inhibitor of the hepatitis C virus NS5B RNA polymerase. To quantitatively elucidate key metabolic pathways, assess the link between unmeasurable effect site concentrations and viral load reduction, and evaluate the influence of intrinsic and extrinsic factors on pharmacokinetics and pharmacodynamics, a model‐informed drug development (MIDD) framework was initiated at an early stage. Originally scoped as a modeling effort focused on minimal physiologically based pharmacokinetic and covariate analyses, this project turned into a collaborative effort focused on gaining a deeper understanding of the data from drug metabolism, biopharmaceutics, pharmacometrics, and clinical pharmacology perspectives. This article presents an example of the practical execution of a MIDD‐based, cooperative multidisciplinary modeling approach, creating a model that grows along with the team's integrated knowledge. Insights gained from this process could be used in forming optimal collaborations between disciplines in drug development for other investigative compounds.

Background Prophylaxis with factor VIII (FVIII) should be individualized based on patient characteristics, including FVIII pharmacokinetics. Population pharmacokinetic (popPK) modeling simplifies pharmacokinetic studies by obviating the need for multiple samples. Objective The objective of this study was to characterize the pharmacokinetics and inter-individual variability (IIV) of BAY 94-9027 in relation to patient characteristics in support of a popPK-tailored approach, including identifying the optimal number and timing of pharmacokinetic samples. Methods Pharmacokinetic samples from 198 males (aged 2‒62 years) with severe hemophilia A, enrolled in BAY 94-9027 clinical trials, were analyzed. Baseline age, height, weight, body mass index, lean body weight (LBW), von Willebrand factor (VWF) level, and race were evaluated. A popPK model was developed and used to simulate pharmacokinetic endpoints difficult to observe from measured FVIII levels, including time to maintain FVIII levels above 1, 3, and 5 IU/dL after different BAY 94-9027 doses. Results A one-compartment model adequately described BAY 94-9027 pharmacokinetics. Clearance and central volume of distribution were significantly associated with LBW; clearance was inversely correlated with VWF. Due to the monophasic pharmacokinetics and well-understood IIV sources, identification of patient pharmacokinetics was achievable with sparse blood sampling. Median predicted time to maintain FVIII levels > 1 IU/dL in patients aged ≥ 12 years ranged from 120.1 to 127.2 h after single BAY 94-9027 doses of 45‒60 IU/kg. Conclusions This analysis evaluated the pharmacokinetics of BAY 94-9027 and its sources of IIV. Using the model, determination of individual patient pharmacokinetics was possible with few FVIII samples, and a sparse sampling design to support pharmacokinetic-guided dosing was identified.

Ulcerative Colitis (UC) is an inflammatory bowel disease typically affecting the colon. Patients with active UC have elevated tumor necrosis factor (TNF) concentrations in serum and colonic tissue. Infliximab is a monoclonal antibody directed against TNF and binds with high affinity. Target-mediated drug disposition (TMDD) is reported for monoclonal antibodies meaning that their pharmacokinetics are affected by high target affinity. Here, a TMDD model is proposed to describe the interaction between infliximab and TNF in UC patients. Data from 20 patients with moderate to severe UC was used. Patients received standard infliximab induction therapy (5 mg kg−1) at week 0, followed by infusions at week 2 and 6. IFX, anti-drug antibodies and TNF serum concentrations were measured at day 0 (1 h after infusion), 1, 4, 7, 11, 14, 18, 21, 28 and 42. A binding model, TMDD model, and a quasi-steady state (QSS) approximation were evaluated using nonlinear mixed effects modeling (NONMEM). A two-compartment model best described the concentration–time profiles of infliximab. Typical clearance of infliximab was 0.404 L day−1 and increased with the presence of anti-drug antibodies and with lower albumin concentrations. The TMDD-QSS model best described the pharmacokinetic and pharmacodynamics data. Estimate for TNF baseline (Bmax was 19.8 pg mL−1 and the dissociation constant (Kss) was 13.6 nM. This model could eventually be used to investigate the relationship between suppression of TNF and the response to IFX therapy.

Background and Objective Midazolam is used to sedate children during extracorporeal membrane oxygenation (ECMO). Pharmacokinetic changes are expected because of extracorporeal circulation and maturation. We present a population pharmacokinetic model for midazolam and its major metabolites in neonates during venoarterial ECMO. Methods We studied 20 neonates on venoarterial ECMO, with a median postnatal age of 0.79 (range 0.17–5.8) days and a bodyweight of 3.0 (range 2.7–3.9) kg at the onset of ECMO. The median ECMO duration was 124 (range 70–275) hours. Serum concentrations were measured at the initiation and discontinuation of the midazolam infusion (100–300 μg/kg/h). Analysis of concentrations of midazolam, 1-hydroxymidazolam and its glucuronide were performed using nonlinear mixed-effects modelling. A two-compartment model for midazolam and a one-compartment model for the metabolites 1-hydroxymidazolam and hydroxymidazolam glucuronide adequately described the data, with allometric scaling of all parameters. Results Following the start of ECMO, the volume of distribution of midazolam increased from 4.29 to 14.6 L/3kg, with an elimination half-life of 1.85 hours. The median midazolam and 1-hydroxymidazolam clearance values increased 3-fold within the first 5 days (up to 1.38 and 5.31 L/h/3 kg, respectively), whereas hydroxymidazolam glucuronide clearance remained constant at 0.18 L/h/3 kg. Interpatient variability estimates of midazolam, 1-hydroxymidazolam and hydroxymidazolam glucuronide clearance and midazolam and hydroxymidazolam glucuronide volumes of distribution varied between 87% and 129%. Concomitant inotropic infusion increased hydroxymidazolam glucuronide clearance by 23%. Conclusion After allometric scaling, clearance of midazolam and 1-hydroxymidazolam increases as a result of maturation or recovery from critical illness. In ECMO patients weighing 2.7–3.9 kg, continuously infused midazolam doses of 300 μg/kg/h for 6 hours and 150 μg/kg/h thereafter provide adequate serum concentrations for sedation. The dose must be increased substantially after 5–7 days. Hydroxymidazolam glucuronide accumulates during ECMO, providing an increased proportion of the overall effect, up to 34% after 7 days. Large unexplained interpatient variability warrants careful titration of sedation and adverse effects.

Objective To describe the pharmacokinetics and exposure of oral sildenafil (SIL) in neonates (2–5 kg) with pulmonary hypertension (PH). Design We included 11 neonates (body weight 2–5 kg, postnatal age 2–121 days) who received SIL and extracorporeal membrane oxygenation (ECMO) treatment for PH. SIL capsules were given via a nasogastric tube. Blood samples were collected via a pre-existing arterial line to quantify SIL and metabolite plasma levels (219 samples). Non-linear mixed effects modelling was used to describe SIL and desmethylsildenafil (DMS) pharmacokinetics. Results A one-compartment model was suitable for SIL and DMS. Interpatient and intrapatient variability for clearance at 100% bioavailability were 87% and 27% (SIL) and 62% and 26% (DMS). Patient weight, postnatal age and post-ECMO time did not explain variability. Concomitant fluconazole use was associated with a 47% reduction in SIL clearance. The exposure expressed as average plasma concentration area under the curve over 24 h (AUC24 (SIL+DMS)) ranged from 625 to 13 579 ng/h/ml. An oral dose of 4.2 mg/kg/24 h would lead to a median AUC24 (SIL+DMS) of 2650 ng/h/ml equivalent to 20 mg three times a day in adults. Interpatient variability was large, with a simulated AUC24 (SIL+DMS) range (10th and 90th percentiles) of 1000–8000 ng/h/ml. Conclusions SIL pharmacokinetics are highly variable in post-ECMO neonates and infants. In a median patient, the current dose regimen of 0.5–2.0 mg/kg four times a day leads to an exposure comparable to the recommended adult dose of 20 mg four times a day. Careful dose titration, based on efficacy and the occurrence of hypotension, remains necessary. Follow-up research should include appropriate pharmacodynamic endpoints, with a population pharmacokinetic/pharmacodynamic analysis to assign a suitable exposure window or target concentration.