Pharmacokinetic-pharmacodynamic analysis of drug liking blockade by buprenorphine subcutaneous depot (CAM2038) in participants with opioid use disorder.

Buprenorphine is used to treat opioid use disorder (OUD). Weekly and monthly subcutaneous long-acting buprenorphine injections (CAM2038) provide more stable buprenorphine plasma levels and reduce the treatment burden, misuse, and diversion associated with sublingual transmucosal buprenorphine formulations. To characterize the pharmacokinetic/pharmacodynamic (PK/PD) relationship, a maximum inhibition (Imax) model was developed relating CAM2038 buprenorphine plasma concentration to drug liking maximum effect (Emax) visual analog scale (VAS; bipolar) score after intramuscular hydromorphone administration. Data included time-matched observations of buprenorphine plasma concentration and drug liking Emax VAS score after hydromorphone 18 mg administration in 47 non-treatment-seeking adults with moderate to severe OUD in a phase 2 study. Analysis used non-|linear mixed-effects modeling (NONMEM®). The final Imax model adequately described the PK/PD relationship between buprenorphine plasma concentration and drug liking Emax VAS score. Simulations showed drug liking was effectively blocked at low buprenorphine plasma concentrations (0.4 ng/mL) where the upper 95% confidence interval of the drug liking Emax VAS score was below the pre-defined 11-point complete blockade threshold. The buprenorphine plasma concentration required to achieve 90% of the maximal effect (IC90) of drug liking was 0.675 ng/mL. Interindividual variability in responses to buprenorphine was observed; some participants experienced fluctuating responses, and a few did not achieve drug liking blockade even with higher buprenorphine plasma concentrations. This affirms the need to individualize treatment and titrate doses for optimal treatment outcomes. PK/PD models were also developed for desire to use VAS and Clinical Opiate Withdrawal Scale (COWS) scores, with results aligned to those for drug liking.

External validation of population pharmacokinetic models of gentamicin in paediatric population from preterm newborns to adolescents.

The aim of this study was to externally validate the predictive performance of published population pharmacokinetic models of gentamicin in all paediatric age groups, from preterm newborns to adolescents. We first selected published population pharmacokinetic models of gentamicin developed in the paediatric population with a wide age range. The parameters of the literature models were then re-estimated using the PRIOR subroutine in NONMEM®. The predictive ability of the literature and the tweaked models was evaluated. Retrospectively collected data from a routine clinical practice (512 concentrations from 308 patients) were used for validation. The models with covariates characterising developmental changes in clearance and volume of distribution had better predictive performance, which improved further after re-estimation. The tweaked model by Wang 2019 performed best, with suitable accuracy and precision across the complete paediatric population. For patients treated in the intensive care unit, a lower proportion of patients would be expected to reach the target trough concentration at standard dosing. The selected model could be used for model-informed precision dosing in clinical settings where the entire paediatric population is treated. However, for use in clinical practice, the next step should include additional analysis of the impact of intensive care treatment on gentamicin pharmacokinetics, followed by prospective validation.

Population pharmacokinetics of cisplatin in small cell lung cancer patients guided with informative priors.

PURPOSE: Cisplatin-etoposide treatment is recommended as a first line in small cell lung cancer patients (SCLC). However, the prognosis is poor and the dosing is not tailored beyond the body surface area, which is related with indeterminate cisplatin exposure-response relationship. We aimed to evaluate cisplatin pharmacokinetics (PK) and the exposure to unbound cisplatin in SCLC patients using the informative priors, and assess the relationship between the cisplatin exposure and probability of neutropenia. METHODS: Observational clinical study was performed including 17 cisplatin-treated SCLC patients. External population cisplatin PK models were identified and NONMEM® software and $PRIOR subroutine were used for the model evaluation. The bias and precision of the model-predicted cisplatin concentrations were evaluated. The best models were combined in a final model including several sets of informative priors, which was used to estimate individual cisplatin exposure, analyze the relationship between the exposure and neutropenia and simulate several cisplatin dosing regimens in a virtual patient cohort. RESULTS: The models by Urien with the informative priors best fitted the data. The individual cisplatin exposure ranged between 2430 and 4560 µg*h/L. There was a trend of increasing probability of neutropenia and febrile neutropenia with increasing cisplatin exposure. Approximately 50%, 75% and 90% of patients receiving 60 mg/m2, 70 mg/m2 and 80 mg/m2, respectively, achieved the previously identified exposure threshold of 2860 µg*h/L. CONCLUSION: We developed a tool to individualize cisplatin dosing based on the estimated probability of neutropenia. The benefit of more intense dosing regimens in SCLC patients should be further assessed.

Relative bioavailability enhancement of simvastatin via dry emulsion systems: Comparison of spray drying and fluid bed layering technology.

Comprehensive comparisons of similar lipid based drug delivery systems produced by different technologies are scarce. Spray drying and fluid bed layering technologies were compared with respect to the process and product characteristics of otherwise similar simvastatin loaded dry emulsion systems. Fluid bed layering provided higher process yield (83.3% vs 71.5%), encapsulation efficiency (80.0% vs 68.4%), relative one month product stability (93.8% vs 85.5%), larger and more circular particles (336 µm vs 56 µm) and lower median oil droplet size after product reconstitution in water (2.85 µm vs 4.27 µm), compared to spray drying. However, spray dried products exhibited higher drug content (22.2 mg/g vs 9.34 mg/g). An in-vivo pharmacokinetic study in rats was performed and a pharmacokinetic model was developed in order to compare the optimised simvastatin loaded dry emulsion systems, a simvastatin glyceride mimetic loaded in the dry emulsion and a simvastatin loaded SMEDDS with a reference physical mixture. Of the formulation tested, fluid bed layered pellets excelled and provided a 115% relative increase in bioavailability. Among the two technologies, fluid bed layering provided dry emulsion products with higher relative bioavailability and better product characteristics for further processing into final dosage forms.

Ustekinumab Dosing Individualization in Crohn's Disease Guided by a Population Pharmacokinetic-Pharmacodynamic Model.

Ustekinumab is a monoclonal antibody used in Crohn's disease (CD). Dose optimization in case of non-response and the role of pharmacokinetic-pharmacodynamic (PK-PD) monitoring remain unresolved dilemmas in clinical practice. We aimed to develop a population PK-PD model for ustekinumab in CD and simulate efficacy of alternative dosing regimens. We included 57 patients and recorded their characteristics during 32 weeks after starting with ustekinumab therapy. Serum ustekinumab concentration was prospectively measured and fecal calprotectin (FC) concentration was used to monitor the disease activity. Ustekinumab PK-PD was described by a two-compartment target-mediated drug disposition model linked to an indirect response model. Lower fat-free mass, higher serum albumin, previous non-exposure to biologics, FCGR3A-158 V/V variant and lower C-reactive protein were associated with higher ustekinumab exposure. Model-based simulation suggested that 41.9% of patients receiving standard dosing achieve biochemical remission at week 32. In patients not achieving remission with standard dosing at week 16, transition to 4-weekly subcutaneous maintenance dosing with or without intravenous reinduction resulted in comparably higher remission rates at week 32 (51.1% vs. 49.2%, respectively). Our findings could be used to guide stratified ustekinumab treatment in CD, particularly in patients with unfavorable characteristics, who might benefit from early transition to 4-weekly maintenance dosing.

Ustekinumab concentrations shortly after escalation to monthly dosing may identify endoscopic remission in refractory Crohn's disease.

OBJECTIVES: Some patients with Crohn's disease do not achieve remission with the approved maintenance dosing of ustekinumab every 8 weeks, possibly due to insufficient drug exposure. We aimed to study the exposure-response relationship for endoscopic remission and biomarker normalization with ustekinumab dose escalation to every 4 weeks. METHODS: Out of 135 consecutive patients, 44 with active Crohn's disease despite standard maintenance dosing [at least one of C-reactive protein (CRP) >5 mg/L, fecal calprotectin >100 mg/kg, simple endoscopic score (SES) for Crohn's disease >3] underwent dose escalation to every 4 weeks. Subsequent endoscopic remission (SES-CD ≤3 without ulceration) and biomarker normalization were compared against ustekinumab concentrations. RESULTS: Dose escalation led to endoscopic remission in 28.6% (8/28), CRP normalization 29.2% (7/24) and fecal calprotectin normalization 51.7% (15/29) of patients. Ustekinumab concentrations after escalation were higher in patients with endoscopic remission (6.90 vs. 4.29 mg/L; P = 0.025) and fecal calprotectin normalization (6.65 vs. 3.74 mg/L; P = 0.001). A threshold of 6.00 mg/L identified endoscopic remission [area under the receiver operating curve (AUROC): 0.775; 95% confidence interval (CI), 0.551-0.999), a threshold of 4.40 mg/L (AUROC 0.755; 95% CI, 0.545-0.964) two months after escalation identified patients with fecal calprotectin normalization at the end of follow-up. Concentrations <3.5 mg/L after escalation precluded endoscopic remission or biomarker normalization. CONCLUSION: Endoscopic remission was associated with higher ustekinumab concentrations after dose escalation. Patients with concentrations <3.5 mg/L after dose escalation are unlikely to achieve endoscopic remission or biomarker normalization.

The Evolving Role of Microsampling in Therapeutic Drug Monitoring of Monoclonal Antibodies in Inflammatory Diseases.

Monoclonal antibodies (mAbs) have been extensively developed over the past few years, for the treatment of various inflammatory diseases. They are large molecules characterized by complex pharmacokinetic and pharmacodynamic properties. Therapeutic drug monitoring (TDM) is routinely implemented in the therapy with mAbs, to monitor patients' treatment response and to further guide dose adjustments. Serum has been the matrix of choice in the TDM of mAbs and its sampling requires the visit of the patients to laboratories that are not always easily accessible. Therefore, dried blood spots (DBS) and various microsampling techniques have been suggested as an alternative. DBS is a sampling technique in which capillary blood is deposited on a special filter paper. It is a relatively simple procedure, and the patients can perform the home-sampling. The convenience it offers has enabled its use in the quantification of small-molecule drugs, whilst in the recent years, studies aimed to develop microsampling methods that will facilitate the TDM of mAbs. Nevertheless, hematocrit still remains an obstacle that hinders a more widespread implementation of DBS in clinical practice. The introduction of novel analytical techniques and contemporary microsampling devices can be considered the steppingstone to the attempts made addressing this issue.

Peak Concentrations of Ustekinumab After Intravenous Induction Therapy Identify Patients With Crohn's Disease Likely to Achieve Endoscopic and Biochemical Remission.

BACKGROUND & AIMS: Little is known about the relationship between ustekinumab exposure during the first 2 weeks of treatment and outcomes of patients with Crohn's disease (CD). We investigated the relationship between serum concentrations of ustekinumab during the first 2 weeks of treatment and endoscopic and biochemical remission in patients with CD. METHODS: In a prospective observational study, we measured concentrations of ustekinumab in serum samples from 41 consecutive patients who started treatment with ustekinumab (approximately 6 mg/kg, intravenously, then 90 mg every 8 weeks), due to endoscopic markers of active CD, at a single center from October 2017 through January 2019. We measured ustekinumab exposure parameters during the first 2 weeks (peak concentration measured immediately after intravenous infusion, week 2 concentration, and area under the curve through week 2). We investigated the correlation between these parameters and endoscopic remission (simple endoscopic score for CD scores of 3 or less without ulceration, assessed centrally) and biochemical remission (level of fecal calprotectin below 100 mg/kg) using the Mann-Whitney U test. RESULTS: Endoscopic remission was achieved in 10 patients (24.4%) at week 24; biochemical remission was achieved in 17 patients (41.5%) at week 8, 17 patients (41.5%) at week 16, and 21 patients (51.2%) at week 24. Peak concentrations associated with endoscopic remission (area under the receiver operating characteristic curve, 0.717; 95% CI, 0.517-0.916); 6 of 13 patients (46%) with peak concentrations above 105 µg/mL (upper tercile) achieved endoscopic remission, compared with only 1 of 14 patients (7%) with peak concentrations below 88 µg/mL (lower tercile). All exposure parameters during the first 2 weeks were associated with biochemical remission. There was no significant difference between the associations of peak concentrations, week-2 concentrations, area under the curve through week 2, or later exposure measures (at weeks 4 and 8) with biochemical or endoscopic remission. CONCLUSIONS: In a prospective study, we found that serum concentrations of ustekinumab as early as 1 hour after intravenous infusion might be used to identify patients with CD most likely to achieve endoscopic remission. This early measurement might be used to optimize treatment of CD.

Synovial fluid interleukin-6 is not superior to cell count and differential in the detection of periprosthetic joint infection.

AIMS: Synovial fluid white blood cell (WBC) count and percentage of polymorphonuclear cells (%PMN) are elevated at periprosthetic joint infection (PJI). Leucocytes produce different interleukins (IL), including IL-6, so we hypothesized that synovial fluid IL-6 could be a more accurate predictor of PJI than synovial fluid WBC count and %PMN. The main aim of our study was to compare the predictive performance of all three diagnostic tests in the detection of PJI. METHODS: Patients undergoing total hip or knee revision surgery were included. In the perioperative assessment phase, synovial fluid WBC count, %PMN, and IL-6 concentration were measured. Patients were labeled as positive or negative according to the predefined cut-off values for IL-6 and WBC count with %PMN. Intraoperative samples for microbiological and histopathological analysis were obtained. PJI was defined as the presence of sinus tract, inflammation in histopathological samples, and growth of the same microorganism in a minimum of two or more samples out of at least four taken. RESULTS: In total, 49 joints in 48 patients (mean age 68 years (SD 10; 26 females (54%), 25 knees (51%)) were included. Of these 11 joints (22%) were infected. The synovial fluid WBC count and %PMN predicted PJI with sensitivity, specificity, accuracy, PPV, and NPV of 82%, 97%, 94%, 90%, and 95%, respectively. Synovial fluid IL-6 predicted PJI with sensitivity, specificity, accuracy, PPV, and NPV of 73%, 95%, 90%, 80%, and 92%, respectively. A comparison of predictive performance indicated a strong agreement between tests. CONCLUSIONS: Synovial fluid IL-6 is not superior to synovial fluid WBC count and %PMN in detecting PJI.Level of Evidence: Therapeutic Level IICite this article: Bone Jt Open 2020;1-12:737-742.

Electromagnetic navigation system for acetabular component placement in total hip arthroplasty is more precise and accurate than the freehand technique: a randomized, controlled trial with 84 patients.

Background and purpose - The accuracy of conventional navigation systems depends on precise registration of bony landmarks. We investigated the clinical use of electromagnetic navigation (EMN), with a unique device for precise determination of the anterior pelvic plane. Patients and methods - We randomly allocated patients scheduled for total hip arthroplasty into 2 groups of 42 patients each. In the study group, cups were placed at the predetermined target angles (inclination: 42.5°; anteversion: 15°) with the support of EMN. In the control group, cups were placed freehand aiming at the same target angles. Postoperatively the true position of the cup was determined using computed tomography scan of the pelvis. Precision (root mean squared error, RMSE) bias (mean bias error, ME), accuracy, and duration of surgery were compared between the methods. Results - Cup anteversion was more accurate and precise in the navigated group. The ME in the navigated and freehand group was -1.7° (95% CI -2.4 to 1.1) and -4.5° (CI -6.5 to 2.5), respectively. The RMSE in the navigated and freehand group was 2.8° (CI 2.3-3.2) and 8.0° (CI 6.3-9.5), respectively. The inclination was also more precise in the navigated group, with the RMSE in the navigated and freehand group at 4.6° (CI 3.4-5.9) and 6.5° (CI 5.4-7.5), respectively. The accuracy of the inclination and the duration of surgeries were similar between the groups. Interpretation - Cup placement with the help of EMN is more precise than the freehand technique and it does not affect the duration of surgery.

Advanced flow cell design for in vitro release testing of mucoadhesive buccal films.

Films for buccal application are a slowly emerging new platform for drug delivery. There remains a lack of analytical techniques for the determination of in vitro active pharmaceutical ingredient release. The aim here was to develop an alternative method to the commonly used United States Pharmacopoeia (USP) 2 method, based on the flow-through cell. This system extends the release time and enables more detailed sample discrimination according to formulation. It could be used as a tool for in vivo prediction of drug release rates from buccal film formulations. The flow cell contains two chambers separated by a membrane through which the released active pharmaceutical ingredient is measured. Vital system variables and their effects on the release rate of the model active pharmaceutical ingredient are presented for formulations based on sodium alginate polymer. The method reflects the differences between films and is shown to be discriminatory for evaluation of buccal formulations.

A review of population pharmacokinetic models of gentamicin in paediatric patients.

WHAT IS KNOWN AND OBJECTIVES: Gentamicin is often used for the treatment of Gram-negative infections. Due to pharmacokinetic variability in paediatric patients, appropriate dosing of gentamicin in the paediatric population is challenging. This article reviews published population pharmacokinetic models of gentamicin in paediatric patients, identifies covariates that significantly influence gentamicin pharmacokinetics, and determines whether there is a consensus on proposed dosing for intravenous gentamicin in this population. METHODS: The PubMed database was searched for articles published until the end of 2017. If the articles described population pharmacokinetic models of gentamicin in the paediatric population (after intravenous administration of gentamicin), the following data were extracted: type of study, year of publication, population characteristics and number of patients, gentamicin dosing, total number of gentamicin (serum and/or plasma) concentrations, type of population modelling approach, developed model with pharmacokinetic parameters and covariates included. RESULTS AND DISCUSSION: In most of the studies, one- or two-compartment modelling was applied. The mean estimated gentamicin clearance for newborns, infants and the complete paediatric population was 0.048, 0.13 and 0.067 L/h/kg, respectively, and the mean predicted volume of distribution was 0.475, 0.35 and 0.33 L/kg, respectively. The values reflect differences in body composition and kidney maturation within the different paediatric populations. Gentamicin pharmacokinetics were most influenced by age, body size and renal function. WHAT IS NEW AND CONCLUSION: Based on our review, the authors agree on a prolonged dosing interval for preterm and term newborns (up to 48 hours). However, there was no agreement on proposed dosing with respect to gestational age. In general, the proposed daily doses were lower compared to those initially applied for preterm newborns and comparable to those for term newborns. For infants and children, the dosing interval remained unchanged (24 hours), but the proposed daily doses were higher than actually applied. When differences in the paediatric population are considered and an appropriate population PK model with applicable covariates is applied, dosing can be individualized. In the future, studies of gentamicin pharmacokinetics in paediatric patients should focus on currently underestimated covariates, such as fat-free mass, concomitantly administered drugs, body temperature and critical illness because these can change gentamicin PK considerably. Consequently, different dosing is required and TDM becomes even more important.

Downregulation of ABCB1 gene in patients with total hip or knee arthroplasty influences pharmacokinetics of rivaroxaban: a population pharmacokinetic-pharmacodynamic study.

PURPOSE: Rivaroxaban is a substrate for ABCB1 transporter and is commonly used in patients undergoing hip or knee replacement surgery for thromboprophylaxis. The objective of this study was to develop a population pharmacokinetic-pharmacodynamic (PK-PD) model to investigate the influence of ABCB1 gene expression and polymorphism on rivaroxaban exposure and anticoagulation effects. METHODS: Five blood samples per patient were collected during 5 days after the surgery for the determination of rivaroxaban concentration in plasma and for determination of prothrombin time and partial thromboplastin time. Non-linear mixed effects model was used for a population PK-PD analysis and for testing covariate effects. RESULTS: A one-compartment PK model with first-order absorption adequately described the pharmacokinetic data. The typical oral clearance (CL/F) was 6.12 L/h (relative standard error, 15.8%) and was associated with ABCB1 expression. Compared to base line before the surgery, a significant ABCB1 downregulation was observed 5 days after the surgery (p < 0.001). Prothrombin time and partial thromboplastin time were both linearly associated to the logarithm of the rivaroxaban plasma concentration. CONCLUSIONS: We confirmed that variable rivaroxaban CL/F is associated with ABCB1 expression, which is in accordance with previous studies on P-glycoprotein involvement in rivaroxaban PK. Furthermore, we observed the downregulation of ABCB1 expression after the surgery. The cause remains unclear and further research is needed to explain the underlying mechanisms.