Background Inter-individual variability in factor VIII (FVIII) peak levels upon desmopressin administration in patients with non-severe hemophilia prompts the need for individual testing before clinical application. The FVIII gene (F8) variant is a strong determinant of the desmopressin response Objectives To investigate the effect of F8 missense variants on FVIII peak levels in response to desmopressin. Methods Machine learning (Shapley Additive exPlanations; SHAP) was applied within a population PK model. Data from 1441 non-severe hemophilia A patients with 55 different F8 variants who underwent desmopressin testing were analyzed. Results Ten F8 missense variants had a significant effect on FVIII peak levels while the rest of the variants were classified as reference, including patients with unknown variants. Variants Pro149Arg, Gly477Val, and Tyr450Asn were associated with a reduced FVIII increase of 24%, 25% and 56%, respectively compared to the reference population (100%); whereas Asn637Ser, Phe2146Ser, Glu132Asp, Arg550His, Ser2030Asn, Thr74Met and Arg717Leu were associated with an augmented FVIII increase of 199%, 219%, 231%, 252%, 265%, 296% and 336% respectively. Following subcutaneous and intranasal administration, FVIII peak levels were 88% and 73% compared to those achieved intravenously (100%). Inclusion of all covariates reduced FVIII peak levels variability from 141.6% to 78.1%. Conclusions This population pharmacokinetic study using machine learning enabled a comprehensive analysis of the effect of F8 variants on FVIII peak levels in response to desmopressin in the context of other covariates, illustrating the complexity of inter-individual variability. These findings provide insights in the underlying molecular mechanisms which influence FVIII peak levels in response to desmopressin.

A significant proportion of patients receiving 5-fluorouracil-based chemotherapy have been reported to experience grade ≥ 3 toxicities, which range from 21 to 76

INTRODUCTION:It remains unclear why up to 30% of ulcerative colitis (UC) patients do not respond to tumor necrosis factor inhibitors (TNFi). Validated biomarkers for nonresponse (N)R) are lacking. Most studies investigating underlying mechanisms do not differentiate between pharmacokinetic and inflammatory mechanisms. We therefore aimed to develop a framework to correct for mucosal drug exposure (MDE) and applied this to mucosal cytokine profiles previously linked to (N)R. METHODS:In a prospective international cohort, we studied patients with active moderate-severe UC starting TNFi treatment. Patients underwent endoscopy before (baseline) and after induction treatment (follow-up). NR was defined as the absence of Mayo endoscopic subscore improvement by central read or need for colectomy. The ratio of mucosal concentrations of TNFi/TNF was used to define high or low MDE. Mucosal concentrations of interleukin-6 (IL-6), Oncostatin M (OSM), interleukin-10 (IL-10), and interleukin-12/23p40 (IL-12/IL-23p40) were measured. RESULTS:Fifty-four UC patients were included (43 infliximab, 11 adalimumab) of whom 39 (72%) were endoscopic responders (after a median treatment of 62 days [48-96]). NR with high MDE had high IL-6 at both time points. R with low MDE exhibited low mucosal IL-10 at baseline. At follow-up, high OSM was associated with NR (irrespective of MDE) and high IL-12/IL-23p40 with R. CONCLUSIONS:We incorporated MDE in mucosal cytokine research to avoid bias due to the insufficient presence of anti-TNF. When applied to mucosal cytokines previously linked to (N)R, IL-6 appears to drive inflammation in TNFi-resistant UC patients, while OSM seems to parallel inflammation and does not cause refractoriness.

Abstract Background Vedolizumab is a monoclonal antibody used for the treatment of inflammatory bowel disease (IBD). The pharmacokinetics (PK) of intravenously (IV) administered vedolizumab have been described previously.1 We aimed to develop a population PK model for subcutaneous (SC) vedolizumab and to evaluate whether current dose regimens are appropriate for SC dosing. Methods Data for model development were prospectively collected in a cohort of 61 patients with IBD receiving IV vedolizumab (300mg at week 0-2-6, thereafter every 4-11 weeks) who switched to SC treatment (108 mg every 2 weeks, Q2W). The PRIOR subroutine in NONMEM2 was used to develop a two-compartment population PK model for IV and SC vedolizumab including linear and non-linear clearance. The model was validated with goodness of fit plots, a visual predictive check and bootstrapping (n = 1000). Final model estimates were used to perform simulations in a virtual population (n = 10 000) with a white blood cell count of 7 x 109/L, randomly sampled serum albumin (mean = 44 g/L, SD = 3.0) and bodyweight (mean 77 kg, SD = 14), based on the distribution of the original dataset. Trough concentrations for an IV regimen of 300 mg vedolizumab once in 8 weeks were compared with SC regimens of 108 mg once in 2, 3, 4 and 5 weeks. For SC vedolizumab, we defined a target serum concentration of 26 mg/L, based on previously reported exposure-efficacy data.3 Results A patient with a bodyweight of 70 kg, serum albumin of 40 g/L and a white blood cell count of 7 x 109/L had a bioavailability of 66.8%, an absorption rate constant of 0.0938/day and a linear clearance of 0.157 L/day. The inter-individual variability for linear clearance was 22.9%. Most important predictors for linear clearance were serum albumin with a negative, and bodyweight and white blood cell count with a positive correlation. In the virtual population, 2.3-fold higher average trough concentrations were estimated for the SC-Q2W regimen (32 mg/L) compared to the IV-Q8W regimen (14 mg/L). Trough concentrations of at least 26 mg/L were achieved in 76% of virtual patients receiving SC vedolizumab every 2 weeks. Virtual patients with a serum vedolizumab concentration higher than 42 mg/L with Q2W dosing could de-escalate to Q3W, while still achieving a trough concentration of 26 mg/L (18% of virtual patients). Conclusion The development and evaluation of a population PK model for IV and SC vedolizumab was successful. This model could be used in the considerations of an extended SC dose regimen. Our results highlight the importance of defining clear targets for SC vedolizumab in clinical practice. References 1.Rosario M, Dirks NL, Gastonguay MR, et al. Population pharmacokinetics-pharmacodynamics of vedolizumab in patients with ulcerative colitis and Crohn’s disease. Aliment Pharmacol Ther. 2015;42(2):188-202. doi:10.1111/APT.13243 2.Gisleskog PO, Karlsson MO, Beal SL. Use of Prior Information to Stabilize a Population Data Analysis. J Pharmacokinet Pharmacodyn. 2002;29(6). 3.D’Haens G, Rosario M, Polhamus D, et al. Exposure–efficacy relationship of vedolizumab subcutaneous and intravenous formulations in Crohn’s disease and ulcerative colitis. Expert Review of Clinical Pharmacology. 2024;17(4):403-412. doi:10.1080/17512433.2024.2318465

Abstract Background Up to 40% of patients with acute severe ulcerative colitis (ASUC) do not respond to infliximab (IFX)(1). Insufficient drug exposure with low IFX serum concentrations is associated with non-response (1, 2). We investigated whether personalised TDM-driven induction dosing of IFX was superior to standard dosing. Methods In this prospective open-label, multi-centre randomised controlled trial (Netherlands, Norway and Ireland), hospitalised adult IFX-naïve and steroid-refractory ASUC patients were randomised 1:1 to standard (SD) or personalised dosing of IFX (PD). After an initial 5 mg/kg IFX infusion, SD consisted of 5 mg/kg IFX at week 2 and 6. In the PD group, additional 5 mg/kg IFX infusions were administered guided by a Bayesian pharmacokinetic algorithm (iDose) aiming at IFX serum concentrations >28 ug/mL from day 0-28 and >15 ug/mL from day 29-42 (measured with Quantum Blue IFX rapid test). After day 42, all patients received 5 mg/kg IFX maintenance every 8 weeks until day 182, with escalation at physician’s discretion. The primary composite endpoint was clinical and endoscopic response at day 42 (Lichtiger score <10 and ≥3 points decrease from baseline and UCEIS ≥2 points decrease with double central endoscopy read and adjudication). Key secondary endpoints included day 42 clinical response, day 42 endoscopic response, day 182 clinical remission (Lichtiger score ≤3), day 182 endoscopic remission (UCEIS ≤1 on all components), and safety (SAEs). Endoscopies were performed at baseline, day 42 and 182. Results 48 patients were included and received study treatment (23 PD/25 SD), 31 of whom completed treatment through week 26 (19 PD/12 SD). Median cumulative IFX dose until day 42 was 18.41 mg/kg [14.77, 20.27] for PD vs 13.79 mg/kg [10.38, 14.82] for SD (Table 1). The primary composite endpoint of clinical and endoscopic response at day 42 was not met (13/23 (56.5%) in PD vs 11/25 (44.0%) in SD; p=0.564) (Figure 1). PD showed a higher day 42 clinical response vs SD (21/23 (91.3%) vs 16/25 (64.0%); p=0.039), Day 42 endoscopic response was observed in 13/23 (56.5%) in PD and 11/25 (44.0%) in SD (p=0.564). Numerically more patients on PD had day 182 clinical remission (14/23 (60.9%) vs 9/25 (36.0%); p=0.148) and endoscopic remission (15/23 (65.2%) vs 9/25 (36.0%); p=0.082) compared to SD. SAEs occurred in 3/23 (13.0%) of patients on PD vs 5/25 (20.0%) of patients on SD (p=0.703) and included infection (2/23 (8.7%) vs 1/25 (4.0%)), thromboembolic event (0 vs 1/25 (4.0%)), colectomy (1/23 (4.4%) vs 2/25 (8.0%)), and death (0 vs 1/25 (4.0%)). Following an interim analysis, the trial was discontinued based on futility. Conclusion Personalised dosing of infliximab was not superior to standard dosing in acute severe ulcerative colitis. References 1.Seow CH, Newman A, Irwin SP, Steinhart AH, Silverberg MS, Greenberg GR. Trough serum infliximab: a predictive factor of clinical outcome for infliximab treatment in acute ulcerative colitis. Gut. 2010;59(1):49-54. 2.Papamichael K, Van Stappen T, Vande Casteele N, Gils A, Billiet T, Tops S, et al. Infliximab Concentration Thresholds During Induction Therapy Are Associated With Short-term Mucosal Healing in Patients With Ulcerative Colitis. Clin Gastroenterol Hepatol. 2016;14(4):543-9.

Pharmacokinetic (PK)-guided dosing of factor concentrates in patients with haemophilia A is generally recommended for the optimisation of prophylac- tic treatment. PK-guided dosing can also be useful in the perioperative setting, where guidelines advise to keep factor VIII (FVIII) activity levels within tight target ranges to prevent bleeding. Previous studies suggest changes in FVIII PK following medical procedures as well as potential time-dependent effects, meaning that population PK models specific to the perioperative setting are required. In this study, we use data from haemophilia A patients collected during the prophylactic and perioperative setting to identify covariates that explain changes in FVIII PK. Additionally, we use machine learning methods to find potential time-dependent effects on FVIII clearance. Perioperative FVIII clearance was generally lower compared to the prophylactic setting. Covariates related to the complexity of the medical procedures were correlated to larger decreases in clearance. Importantly, subjects undergoing more complex procedures also depicted potentially relevant time-dependent effects on clearance. These effects could be highly variable between subjects. Directly using PK parameters obtained from the prophylactic setting resulted in relatively high mean absolute percentage error (MAPE) at 26.3\%, while the perioperative model including time-dependent effects depicted markedly reduced error (10.3\%). The presence of high variability between subjects and potential time-dependent effects complicates the selection of optimal dosing regimens before the start of medical procedures. Our method can be used to optimise treatment in real-time, but close monitoring of FVIII levels will likely remain necessary. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This project was performed as part of the SYMPHONY consortium, which has received funding from the Netherlands Organisation for Scientic Research (NWO) under grant agreement NWA.1160.18.038. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Medisch-Ethische Toetsingscommissie of Amsterdam University Medical Centers waived ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All model code is made available at https://github.com/JanssenaPerioperativeFVIII.

AbstractLimited data are available on VWF activity (VWF:Act) and factor VIII (FVIII:C) levels during delivery after VWF/FVIII concentrate administration in women with von Willebrand disease (VWD). We aimed to evaluate treatment with a specific VWF/FVIII concentrate on factor levels in women with VWD during delivery and the postpartum period. A retrospective single‐center study was conducted between January 1, 2008, and August 1, 2022. Pregnant women treated with Haemate®P during delivery were included if they had ≥2 consecutive VWF:Act and FVIII:C measurements post‐infusion. VWF:Act/FVIII:C levels were compared to predefined target levels. A population pharmacokinetic (PopPK) model was developed, estimating VWF and FVIII pharmacokinetics after Haemate®P administration. Nineteen women were included. Targeted VWF:Act/FVIII:C peak levels were achieved after the first infusion (≥1.00 IU/mL, n = 12; ≥1.50 IU/mL, n = 5), and all VWF:Act/FVIII:C trough levels remained ≥0.50 IU/mL during first 72 h of treatment. All women had pretreatment FVIII:C levels ≥1.00 IU/mL, except one woman with type 2N, which was significantly higher than FVIII:C levels during the third trimester (median increase: 0.42 IU/mL, interquartile range: [0.12–0.92]). FVIII:C trough levels increased during treatment, median 2.05 IU/mL [1.65–2.71]. Nine women (47%) experienced postpartum hemorrhage and no thrombosis occurred. A one‐compartment PopPK model adequately described VWF:Act/FVIII:C levels. Targeted VWF:Act/FVIII:C peak levels were achieved with the prescribed dosing regimens. VWF clearance was similar to that in nonpregnant individuals. Both pretreatment and FVIIIC trough levels during treatment were high with reduced FVIII clearance. Monitoring VWF:Act/FVIII:C levels is recommended for optimizing target levels and enriching the current PopPK model, improving VWF:Act/FVIII:C level predictions, and achieving more effective dosing.

Background: While prophylactic emicizumab therapy is highly effective in preventing bleeding in hemophilia A and generally well-tolerated, the high costs impose a significant financial burden on healthcare systems. Several case series have suggested that current bodyweight-based dosing of emicizumab could be safely reduced, providing similar effectiveness at a lower cost. Aim: Determine whether individualized PK-guided reduced dosing of emicizumab targeting a Ctrough emicizumab concentration of 30±5 μg/mL is non-inferior to conventional bodyweight-based dosing in the prevention of bleeding in hemophilia A patients. Methods: The DosEmi study is an ongoing phase IV, multicenter, prospective, open-label, crossover study comparing 12 months of conventional dosing of emicizumab vs 12 months of PK-guided reduced dosing targeting at concentrations of 30±5 μg/mL (ClinicalTrial.gov - NCT06320626). Study participants were recruited from eight Dutch hemophilia treatment centers from September 1st 2022 onwards. Eligible participants have severe or moderate congenital hemophilia A (FVIII < 6 IU/mL) with and without FVIII-inhibitors; receiving conventional dosing of emicizumab (according to label of 6 mg/kg/4 weeks at varying intervals) for a duration of ≥ 12 months prior to inclusion with good bleeding control, defined as: no spontaneous joint/muscle bleeds in the previous six months and/or a maximum of two treated (traumatic) bleeds in the previous six months. Emicizumab concentrations were determined by a validated liquid chromatography-tandem mass spectrometry method after 12 months on conventional dosing, only patients with an emicizumab trough levels of ≥ 40 μg/mL were eligible for dose reduction. Patients with emicizumab trough levels of 25-39 μg/mL continued their current dose regimen and were followed observationally for 12 months. Patients with emicizumab trough levels of < 25 μg/mL were adjusted in dosing regimen according to local protocol. The interim analysis was scheduled to compare the proportion of patients without treated bleeds during six months of follow-up on conventional dosing to six months on PK-guided dosing using survival analysis, with a predefined non-inferiority criterion of an absolute risk difference of <16%. Patient characteristics were summarized as numbers (%) and medians with interquartile range (IQR, P25-P75). Results: On July 1st 2024, 72 patients were included in the study. Emicizumab concentrations were measured in 30 patients, and the emicizumab dose was reduced in 27 out of 30 patients. The median age of study participants was 52 (IQR 33 - 62) years. All patients had severe hemophilia A, and the majority of patients had no FVIII inhibitors (n=25, 93%). Overall, the emicizumab dose was decreased from a median of 6 (IQR 5.2 - 6.4) mg/kg/4wks to 3.4 (IQR 2.8 - 3.9) mg/kg/4wks. The median follow up during PK-guided dosing was 4.6 (IQR: 3.2 - 10.5) months, of which 13 patients completed the entire six months on PK-guided dosing. Bleeding control remained stable over the follow-up period. The proportion of patients without treated bleeds was 76% during conventional dosing versus 71% during the PK-guided dosing (p=0.222). Similar results were observed with regard to the proportion of patients without treated joint bleeds, 82% versus 87% respectively (p=0.609). All bleeds were traumatic except in one patient who developed a spontaneous ultrasound confirmed muscle bleed on PK-guided dosing. Regarding the safety, no emicizumab related adverse events nor thrombotic events were observed after dose reduction Conclusion: With an absolute risk difference of +5% for absence of bleeding and -4% for absence of joint bleeding, these preliminary interim results suggest that PK-guided reduced dosing of emicizumab at concentrations of 30±5 μg/mL is non inferior to conventional dosing in preventing bleeding in patients with congenital hemophilia A. The definite results from this prespecified interim analysis evaluating the full six months of PK-guided dosing in 25 adult patients will be available in December 2024.

Hemophilia A patients are treated with factor (F) VIII prophylactically to prevent bleeding. In general, dosage and frequency are based on pharmacokinetic measurements. Ideally, an alternative dose adjustment can be based on the hemostatic potential, measured with a thrombin generation assay (TGA), like the Nijmegen hemostasis assay. The objective of this study was to investigate the predicted performance of a previously developed pharmacokinetic–pharmacodynamic model for FVIII replacement therapy, relating FVIII dose and FVIII activity levels with thrombin and plasmin generation parameters. Pharmacokinetic and pharmacodynamic measurements were obtained from 29 severe hemophilia A patients treated with pdVWF/FVIII concentrate (Haemate P®). The predictive performance of the previously developed pharmacokinetic–pharmacodynamic model was evaluated using nonlinear mixed-effects modeling (NONMEM). When predictions of FVIII activity or TGA parameters were inadequate [median prediction error (MPE) > 20

BACKGROUND:The use of concomitant azathioprine may improve efficacy and pharmacokinetic (PK) properties of infliximab (IFX) but is also associated with an increased risk of adverse events. Proactive therapeutic drug monitoring (pTDM) of IFX monotherapy is an alternative strategy to improve PK. The aim of this study was to evaluate whether IFX with an immunomodulator (combo) has PK benefits over IFX-pTDM (mono) in pediatric Crohn's disease (CD). METHODS:This PK analysis included pediatric CD patients who started either IFX combo (TISKids study) or IFX mono with pTDM (REFINE cohort). Combo and mono IFX trough levels (TLs) and antibodies-to-infliximab were assessed at infusion 3, 4, and 5. A population PK model was built to compare IFX PK outcomes (clearance [CL], TLs and cumulative exposure) between combo and mono groups at infusion 4 and 5. Clinical response and steroid-free clinical remission (SFCR) was assessed at infusion 4 and 5. RESULTS:This study included 128 pediatric CD patients (66 mono and 62 combo). At infusion 5, there was no significant difference between mono and combo median TLs 4.1 µg/mL (2.1, 7.8) vs 5.9 µg/mL (3.2, 9.4; P = .14) or median CL 0.26 L/d (0.21, 0.32) vs 0.26 L/d (0.21, 0.33; P = .81). Mono patients had a lower SFCR rate at infusion 5 (53% [31 of 59] vs 80% [32 of 40]; P = .01). Clinical response rates were significantly higher among combo than mono patients at both infusion 4 and 5. CONCLUSIONS:This study suggests that there are no PK differences (TLs and CL) between combo and mono therapy in pediatric CD patients who started IFX.

Background: Guidelines advise 50 % and 25 % dose reduction of the therapeutic nadroparin dose (86 IU/kg) in patients with eGFR 15-29 and 30-60 ml/min respectively. For monitoring, peak anti-Xa levels are suggested. Data lack whether this results in therapeutic anti-Xa levels or in anti-Xa levels that are comparable to those of patients without renal impairment. Aims: To determine dose ranges in patients with renal impairment that result in therapeutic anti-Xa levels and to determine the percentage of the 86 IU/kg dose that results in anti-Xa levels normally occurring in patients without renal impairment. Methods: A retrospective cohort study was conducted in five hospitals. Patients >= 18 years of age, with an eGFR >= 15 ml/min were included. The first correctly sampled peak (i.e. 3-5 h after >= third administration, regardless of dose per patient) was included. Simulated prediction models were developed using multiple linear regression. Results: 770 patients were included. eGFR and hospital affected the association between dose and anti-Xa level. The doses for peak anti-Xa levels of 0.75 IU/ml differed substantially between hospitals and ranged from 55 to 91, 65-359 and 68-168 IU/kg in eGFR 15-29, 30-60 and > 60 ml/min/1.73m(2), respectively. In eGFR 15-29 and 30-60 ml/min/1.73m(2), doses of 75 % and 91 % of 86 IU/kg respectively, were needed for anti-Xa levels normally occurring in patients with eGFR > 60 ml/min. Conclusion: We advise against anti-Xa based dose -adjustments as long as anti-Xa assays between laboratories are not harmonized and an anti-Xa target range is not validated. A better approach might be to target levels similar to eGFR > 60 ml/min/1.73m(2), which are achieved by smaller dose reductions.

Therapeutic drug monitoring (TDM) of elexacaftor, tezacaftor, ivacaftor (ETI) could be a useful tool to increase efficacy and decrease the risk of adverse effects in people with Cystic Fibrosis (pwCF). It is however unclear whether drug exposure should be monitored by assessment of trough (C-min) levels or determination of the area under the curve (AUC). Hence, in this study the correlation between measured C min concentration and AUC was evaluated. Serial plasma samples, including C-min , were drawn after administration of ETI in order to calculate the AUC and assess the correlation between the two parameters. A linear correlation between C- min and AUC 0-24h was found, with Pearson's r correlation coefficients of 0.963, 0.908 and 0.860 for elexacaftor, tezacaftor and ivacaftor, respectively. Exposure of ETI may be monitored by assessment of C( min )levels.

Juvenile idiopathic arthritis (JIA) is a chronic autoimmune disorder that primarily affects the joints in children. Notably, it is known to co-occur with uveitis. Adalimumab, a monoclonal anti-TNF antibody, is effective in treating both conditions. A deeper understanding of the pharmacokinetics (PK) of adalimumab in JIA is crucial to advance in more personalized treatment approaches. The objective of this study is to evaluate the population PK profile of adalimumab in JIA and to explain causes for its variability. Adalimumab and antidrug antibody concentrations were retrospectively retrieved from the charts of patients with JIA. Initially, five literature-based population PK models of adalimumab were evaluated to assess their ability to describe the observed concentration–time profiles in the JIA cohort. These models included one specifically for the pediatric Crohn’s disease population and four derived from studies in adult populations in healthy subjects and rheumatoid arthritis patients. Subsequently, a novel population PK model tailored to the JIA population was developed using NONMEM software. Monte Carlo simulations were then conducted utilizing the final PK model to visualize the concentration–time profile of adalimumab in patients with JIA and the impact of covariates. A cohort of 50 patients with JIA with 78 available adalimumab samples was assessed. The mean age was 11.8 ± 3.9 years, with a median body weight of 49 kg (interquartile range 29.4–59.8 kg). All literature models adequately described the concentration–time profiles in JIA. The best model, which was developed in patients with rheumatoid arthritis during the maintenance phase of treatment, served as a basis for estimating clearance in JIA, resulting in a value of 0.37 L per day per 70 kg. Patient body weight, antidrug antibodies, methotrexate use, CRP level, and comorbidity of uveitis were found to have a significant impact on adalimumab clearance, and these reduced the inter-patient variability from 58.6 to 28.0

This work focusses on extending the deep compartment model (DCM) framework to the estimation of mixed-effects. By introducing random effects, model predictions can be personalized based on drug measurements, enabling the testing of different treatment schedules on an individual basis. The performance of classical first-order (FO and FOCE) and machine learning based variational inference (VI) algorithms were compared in a simulation study. In VI, posterior distributions of the random variables are approximated using variational distributions whose parameters can be directly optimized. We found that variational approximations estimated using the path derivative gradient estimator version of VI were highly accurate. Models fit on the simulated data set using the FO and VI objective functions gave similar results, with accurate predictions of both the population parameters and covariate effects. Contrastingly, models fit using FOCE depicted erratic behaviour during optimization, and resulting parameter estimates were inaccurate. Finally, we compared the performance of the methods on two real-world data sets of haemophilia A patients who received standard half-life factor VIII concentrates during prophylactic and perioperative settings. Again, models fit using FO and VI depicted similar results, although some models fit using FO presented divergent results. Again, models fit using FOCE were unstable. In conclusion, we show that mixed-effects estimation using the DCM is feasible. VI performs conditional estimation, which might lead to more accurate results in more complex models compared to the FO method.

Background Recombinant factor IX Fc fusion protein (rFIX-Fc) is an extended half-life (EHL) factor concentrate administered to haemophilia B patients. So far, a population pharmacokinetic (PK) model has only been published for patients ≥12 years of age. Aim Assess the predictive performance of the published rFIX-Fc population PK model for patients of all ages and develop a model that describes rFIX-Fc PK using real world data. Methods We collected prospective and retrospective data from patients with haemophilia B (FIX activity level ≤5 IU/dL) treated with rFIX-Fc and included in the OPTI-CLOT TARGET study (NTR7523) or United Kingdom (UK)-EHL Outcome Registry (NCT02938156). Predictive performance was assessed by comparing predicted with observed FIX activity levels. A novel population PK model was constructed using nonlinear mixed-effects modelling. Results Real world data was obtained from 37 patients (median age: 16 years, range 2-71) of whom 14 were <12 years of age. Observed FIX activity levels were significantly higher than levels predicted using the published model, with a median prediction error (PE) of -48.8%. The novel model showed a lower median PE (3.4%) and better described rFIX-Fc PK, especially for children <12 years of age. In the novel model, an increase in age was correlated with a decrease in clearance (p<0.01). Conclusion The published population PK model significantly underpredicted FIX activity levels. The novel model better describes rFIX-Fc PK, especially for children <12 years of age. This study underlines the necessity to strive for representative population PK models, thereby avoiding extrapolation outside the studied population.

Previously, we showed that the combination of methotrexate and adalimumab treatment leads to less antidrug antibody development. In this study, we quantify the pharmacokinetics/pharmacodynamics (PK/PD) of adalimumab and evaluate the influence of methotrexate cotreatment. A population PK-PD model was developed using prospective data from 59 patients with psoriasis (baseline PASI = 12.6) receiving adalimumab over 49 weeks. Typical PK and PD parameters and their corresponding interpatient variability were estimated. We performed a covariate analysis to assess whether interpatient variability could be explained by addition of methotrexate and other covariates. In total, 330 PASIs, 252 adalimumab serum concentrations, and 247 antidrug antibody titers were available. Presence of antidrug antibodies (adalimumab group = 46.7%, adalimumab + methotrexate group = 38.7%; P = .031) was correlated with increased adalimumab apparent clearance (P < .001). In the PD model, the use of concomitant methotrexate was borderline to significantly correlated with a decreased half-maximal inhibitory concentration (adalimumab concentration for which clinical response score is reduced by half; P < .10). On the basis of our PK-PD model, concomitant use of methotrexate indirectly increases adalimumab concentration, partially through less antidrug antibodies formation, which may result in better efficacy.

Abstract Background and Aims To prevent rejection kidney transplant recipients are treated with immunosuppressive drugs, like tacrolimus. The dosage needed to reach therapeutic trough levels of tacrolimus greatly varies between patients. Currently, there are two tacrolimus extended-release variants on the market. Tacrolimus-extended release (Tac-ER/Advagraf) and tacrolimus LCPT (Tac-LCPT/Envarsus). Tac-LCPT was developed using Meltdose technology to improve absorption. Studies suggest that with Tac-LCPT therapeutic levels can be reached with a lower total dose as compared to Tac-ER. We aim to investigate if the dose needed to reach therapeutic trough levels of tacrolimus can be reduced when using Tac-LCPT as compared to Tac-ER in patients who need a relatively high dose. Method A prospective open-label switch design study was performed in patients 6 months up to 5 years after receiving a kidney transplant, who received Tac-ER, with therapeutic trough levels, and a concentration/dosage ratio (CDR) &lt;1.05 ng/mlx1/mg. Patients were switched from Tac-ER to Tac-LCPT with a dose reduction of 30% for 3 weeks. After these 3 weeks, they were switched back to their original dose of Tac-ER. Total follow-up was 6 weeks with weekly visits for adjustment of the dosage. The primary outcome was the dose of Tac-LCPT needed to reach therapeutic trough levels as compared to Tac-ER. Secondary outcomes were side effects and pill burden. Results For this preliminary analysis, 8 kidney transplant recipients were included. At baseline, the median age was 52.5 (IQR 44.5, 57.0) years old, 75% of patients were male, and the median number of months after transplantation was 14.2 (IQR 11.50, 16.08). The median dose of Tac-ER needed at baseline was 9.0 mg (IQR 8.0, 11.25) with a CDR of 0.89 (IQR 0.68, 0.92). The tacrolimus dosage needed to reach therapeutic trough levels was significantly lower with Tac-LCPT compared to Tac-ER (5.5 mg vs. 9.5 mg, p = 0.03). However, the patients experiencing side effects and the pill burden did not change between the formulations. The Cmax of Tac-ER and Tac-LCPT varied between patients, with no significant difference between formulations (Fig. 1). At the end of the study, two patients preferred to continue Tac-LCPT, one patient preferred Tac-ER and the remaining patients had no preference. Conclusion In conclusion, the total needed dosage of tacrolimus to obtain therapeutic trough levels with Tac-LCPT is smaller than with Tac-ER. However, this smaller dosage administered did not translate to fewer side effects, a smaller pill burden, or a lower peak concentration. When inclusion is completed, additional pharmacokinetics will be calculated as well as the determination of CYP3A5 polymorphisms.

Background: Desmopressin is frequently used perioperatively in persons with nonsevere hemophilia A. However, increase in factor (F)VIII:C after desmopressin use is interindividually highly variable. Tachyphylaxis has only been reported in test setting for persons with hemophilia A, with a remaining response of approximately 70% after a second dose compared with that after a first dose. Objectives: To study tachyphylaxis of FVIII:C response after multiple administration(s) of desmopressin in perioperative persons with nonsevere hemophilia A. Methods: We studied FVIII:C levels after desmopressin before (day 0 [D0]) and on days 1 (D1) and 2 (D2) after surgery in 26 patients of the DAVID and Little DAVID studies. We studied tachyphylaxis by comparing the responses at D1 and D2 with that at D0. We also assessed the reproducibility of the D0 response in comparison to an earlier performed desmopressin test. Results: The median absolute FVIII:C increase was 0.50 IU/mL (0.35-0.74; n = 23) at D0, 0.21 IU/mL (0.14-0.28; n = 17) at D1, and 0.23 IU/mL (0.16-0.30; n = 11) at D2. The median percentage of FVIII increase after the second administration (D1) compared with the first (D0) was 42.9% (29.2%-52.5%; n = 17) and that of the third (D2) compared with the first (D0) was 36.4% (23.7%-46.9%; n = 11). The FVIII:C desmopressin response at D0 was comparable with the desmopressin test response in 74% of the patients. Conclusion: Tachyphylaxis in the surgical setting was considerably more pronounced than previously reported, with FVIII:C at D1 and D2 of 36% to 43% of the initial response. Our results may have important implications for monitoring repeated desmopressin treatment when used perioperatively.

Prrpose: Cystic fibrosis (CF) is a monogenetic disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein and affecting multiple organs, including the lungs and liver. Almost 90% of people affected carry at least 1 Phe508del CFTR mutation. Medical treatment with the CFTR-modulating drug elexacaftor-tezacaftor-ivacaftor (ETI) has been proven to be efficacious in carriers of at least 1 Phe508del CFTR mutation. Use of ETI in patients with CF (pwCF) and liver cirrhosis is still controversial. Therefore, stepwise introduction of ETI in pwCF and liver cirrhosis Child-Pugh A or B was evaluated using clinical and therapeutic drug monitoring. Methods: Seven consecutive pwCF received ETI. Four dosing steps were defined, at each of which the patients underwent clinical examination, routine blood tests, and therapeutic drug monitoring. Exposure of elexacaftor, tezacaftor, and ivacaftor was assessed by means of determination of AUC. Findings: ETI was successfully introduced and maintained in all pwCF. In those with Child-Pugh B cirrhosis (n = 2), diminishment of the dose as recommended by the label resulted in AUC values that were lower than the mean AUC values in pwCF without hepatic impairment, as reported previously. Implications: Despite the limitations of this small case series, stepwise elevation of ETI dose did not induce clinical adverse effects or increases in serum liver test results under strict clinical follow-up and therapeutic drug monitoring, and may allow tolerable introduction of this therapy in pwCF and cirrhosis Child-Pugh A and possibly B.