Assessment of body mass-related covariates for rifampicin pharmacokinetics in healthy Caucasian volunteers.

PURPOSE: Currently, body weight-based dosing of rifampicin is recommended. But lately, fat-free mass (FFM) was reported to be superior to body weight (BW). The present evaluation aimed to assess the influence of body mass-related covariates on rifampicin's pharmacokinetics (PK) parameters in more detail using non-linear mixed effects modeling (NLMEM). METHODS: Twenty-four healthy Caucasian volunteers were enrolled in a bioequivalence study, each receiving a test and a reference tablet of 600 mg of rifampicin separated by a wash-out period of at least 9 days. Monolix version 2023R1 was used for NLMEM. Monte Carlo simulations (MCS) were performed to visualize the relationship of body size descriptors to the exposure to rifampicin. RESULTS: A one-compartment model with nonlinear (Michaelis-Menten) elimination and zero-order absorption kinetics with a lag time best described the data. The covariate model including fat-free mass (FFM) on volume of distribution (V/F) and on maximum elimination rate (Vmax/F) lowered the objective function value (OFV) by 56.4. The second-best covariate model of sex on V/F and Vmax/F and BW on V/F reduced the OFV by 51.2. The decrease in unexplained inter-individual variability on Vmax/F in both covariate models was similar. For a given dose, MCS showed lower exposure to rifampicin with higher FFM and accordingly in males compared to females with the same BW and body height. CONCLUSION: Our results indicate that beyond BW, body composition as reflected by FFM could also be relevant for optimized dosing of rifampicin. This assumption needs to be studied further in patients treated with rifampicin.

Cefepime Population Pharmacokinetics, Antibacterial Target Attainment, and Estimated Probability of Neurotoxicity in Critically Ill Patients.

Cefepime has been reported to cause concentration-related neurotoxicity, especially in critically ill patients with renal failure. This evaluation aimed to identify a dosing regimen providing a sufficient probability of target attainment (PTA) and the lowest justifiable risk of neurotoxicity in critically ill patients. A population pharmacokinetic model was developed based on plasma concentrations over four consecutive days obtained from 14 intensive care unit (ICU) patients. The patients received a median dose of 2,000 mg cefepime by 30-min intravenous infusions with dosing intervals of every 8 h (q8h) to q24h. A time that the free drug concentration exceeds the MIC over the dosing interval (fT>MIC) of 65% and an fT>2×MIC of 100% were defined as treatment targets. Monte Carlo simulations were carried out to identify a dosing regimen for a PTA of 90% and a probability of neurotoxicity not exceeding 20%. A two-compartment model with linear elimination best described the data. Estimated creatinine clearance was significantly related to the clearance of cefepime in nondialysis patients. Interoccasion variability on clearance improved the model, reflecting dynamic clearance changes. The evaluations suggested combining thrice-daily administration as an appropriate choice. In patients with normal renal function (creatinine clearance, 120 mL/min), for the pharmacodynamics target of 100% fT>2×MIC and a PTA of 90%, a dose of 1,333 mg q8h was found to be related to a probability of neurotoxicity of ≤20% and to cover MICs up to 2 mg/L. Continuous infusion appears to be superior to other dosing regimens by providing higher efficacy and a low risk of neurotoxicity. The model makes it possible to improve the predicted balance between cefepime efficacy and neurotoxicity in critically ill patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT01793012).

Evaluation of patient-reported severity of hand-foot syndrome under capecitabine using a Markov modeling approach.

PURPOSE: The inclusion of the patient's perspective has become increasingly important when reporting adverse events and may assist in management of toxicity. The relationship between drug exposure and toxicity can be quantified by combining Markov elements with pharmacometric models. A minimal continuous-time Markov model (mCTMM) was applied to patient-reported outcomes using hand-foot syndrome (HFS) induced by capecitabine anti-cancer therapy as an example. METHODS: Patient-reported HFS grades over time of 150 patients from two observational studies treated with oral capecitabine were analyzed using a mCTMM approach. Grading of HFS severity was based on the Common Terminology Criteria for Adverse Events. The model was evaluated by visual predictive checks (VPC). Furthermore, a simulation study of the probability of HFS severity over time was performed in which the standard dosing regimen and dose adjustments according to HFS severity were investigated. RESULTS: The VPC of the developed dose-toxicity model indicated an accurate description of HFS severity over time. Individual absolute daily dose was found to be a predictor for HFS. The simulation study demonstrated a reduction of severe HFS using the recommended dose adjustment strategy. CONCLUSION: A minimal continuous-time Markov model was developed based on patient-reported severity of hand-foot syndrome under capecitabine. Thus, a modeling framework for patient-reported outcomes was created which may assist in the optimization of dosage regimens and adjustment strategies aiming at minimizing symptom burden during anti-cancer drug therapy.

A Novel Study Design Using Continuous Intravenous and Intraduodenal Infusions of Midazolam and Voriconazole for Mechanistic Quantitative Assessment of Hepatic and Intestinal CYP3A Inhibition.

The extent of a drug-drug interaction (DDI) mediated by cytochrome P450 (CYP) 3A inhibitors is highly variable during a dosing interval, as it depends on the temporal course of victim and perpetrator drug concentrations at intestinal and hepatic CYP3A expression sites. Capturing the time course of inhibition is therefore difficult using standard DDI studies assessing changes in area under the curve; thus, a novel design was developed. In a 4-period changeover pilot study, 6 healthy men received intraduodenal or intravenous infusions of the CYP3A substrate midazolam (MDZ) at a rate of 0.26 mg/h for 24 hours. This was combined with intraduodenal or intravenous infusion of the CYP3A inhibitor voriconazole (VRZ), administered at rates of 7.5 mg/h from 8 to 16 hours and of 15 mg/h from 16 to 24 hours, after starting midazolam administration. Plasma and urine concentrations of VRZ, MDZ, and its major metabolites were quantified by liquid chromatography-tandem mass spectrometry and analyzed by semiphysiological population pharmacokinetic nonlinear mixed-effects modeling. A model including mechanism-based inactivation of the metabolizing enzymes (maximum inactivation rate constant kinact , 2.83 h-1 ; dissociation rate constant KI , 9.33 µM) described the pharmacokinetics of VRZ well. By introducing competitive inhibition by VRZ on primary and secondary MDZ metabolism, concentration-time profiles, MDZ and its metabolites were captured appropriately. The model provides estimates of local concentrations of substrate and inhibitor at the major CYP3A expression sites and thus of the respective dynamic extent of inhibition. A combination of intravenous and intraduodenal infusions of inhibitors and substrates has the potential to provide a more accurate assessment of DDIs occurring in both gut wall and liver.

Interprofessional Medication Management in Patients With Multiple Morbidities.

BACKGROUND: Medication reviews and medication management are being used more and more around the world to improve medication safety. Both of these tools were originally conceived as pharmaceutical care activities and have recently been developed into interdisciplinary approaches. We studied the efficacy of interprofessional medication management for multimorbid patients that takes their medical conditions, but also their general living situation into account. METHODS: A comprehensive medication management was performed, which involved the collection of information on the drugs each patient took, the way they were stored, the patient's drug intake and handling, and any problems that arose with pharmacotherapy. The interventional approach was evaluated over a period of 15 months in a cluster-randomized controlled trial with a stepped wedge design. The primary endpoint was the quality of pharmacotherapy, as assessed with the Medication Appropriateness Index (MAI). A mixed model was used to analyze efficacy. RESULTS: 162 patients were enrolled in the study; 142 were included in the intention-to-treat analysis (53.3% women, mean age 76.8 ± 6.3 years). The mean total MAI score decreased significantly (p ≤ 0.001) from the control phase (29.21, 95% CI [26.09; 32.33]) to the intervention phase (22.27 [19.00; 25.54]), with an effect strength (Cohen's d) of -0.24 [-0.36; -0.13]. The number of drug-related problems declined as well. CONCLUSION: In this study, interprofessional collaboration increased medication safety. Working across disciplinary boundaries allowed for a decrease in drugrelated problems and brought up aspects outside the purview of the primary care physician.

Priority Setting and Influential Factors on Acceptance of Pharmaceutical Recommendations in Collaborative Medication Reviews in an Ambulatory Care Setting - Analysis of a Cluster Randomized Controlled Trial (WestGem-Study).

BACKGROUND: Medication reviews are recognized services to increase quality of therapy and reduce medication risks. The selection of eligible patients with potential to receive a major benefit is based on assumptions rather than on factual data. Acceptance of interprofessional collaboration is crucial to increase the quality of medication therapy. OBJECTIVE: The research question was to identify and prioritize eligible patients for a medication review and to provide evidence-based criteria for patient selection. Acceptance of the prescribing general practitioner to implement pharmaceutical recommendations was measured and factors influencing physicians' acceptance were explored to obtain an impression on the extent of collaboration in medication review in an ambulatory care setting. METHODS: Based on data of a cluster-randomized controlled study (WestGem-study), the correlation between patient parameters and the individual performance in a medication review was calculated in a multiple logistic regression model. Physician's acceptance of the suggested intervention was assessed using feedback forms. Influential factors were analyzed. RESULTS: The number of drugs in use (p = 0.001), discrepancies between prescribed and used medicines (p = 0.014), the baseline Medication Appropriateness Index score (p<0.001) and the duration of the intervention (p = 0.006) could be identified as influential factors for a major benefit from a medication review, whereas morbidity (p>0.05) and a low kidney function (p>0.05) do not predetermine the outcome. Longitudinal patient care with repeated reviews showed higher interprofessional acceptance and superior patient benefit. A total of 54.9% of the recommendations in a medication review on drug therapy were accepted for implementation. CONCLUSIONS: The number of drugs in use and medication reconciliation could be a first rational step in patient selection for a medication review. Most elderly, multimorbid patients with polymedication experience a similar chance of receiving a benefit from a medication review. Longitudinal patient care should be preferred over confined medication reviews. The acceptance of medication reviews by physicians supports further implementation into health care systems. TRIAL REGISTRATION: ISRCTN ISRCTN41595373.

Analysis of drug-related problems in three departments of a German University hospital.

BACKGROUND: During the last decades, pharmaceutical care services have been developed and implemented to optimize drug therapies and ensure medication safety. To investigate the need for pharmaceutical care services, drug-related problems can be measured. OBJECTIVE: Thus, the aim of this study was to analyse number, type and occurrence of drug-related problems in different clinical departments. SETTING: A pharmaceutical care service was established on general wards in Urology, Neurology and Gastroenterology at the University Hospital RWTH Aachen, Germany. METHOD: For each of a total of 306 patients, a pharmacist conducted an extended medication history, performed medication reconciliation, conducted medication safety checks and if drug-related problems were discovered, gave valid recommendations to the attending healthcare team. Drug-related problems were classified using the APS-Doc system. For statistical analyses, SAS(®) 9.1.3, SAS Institute, Cary NC, USA was applied. The project was approved by the local ethics committee. MAIN OUTCOME MEASURE: Type, occurrence and frequency of DRP in different medical departments. RESULTS: On average, 2.3 drug-related problems per patient were documented for all three departments. Drug-related problems were found in each category of the APS-Doc system. The most pronounced drug-related problems found were drug-drug interactions (34.6 %). 37 % of the identified drug-related problems occurred before hospital admission, 27 % during transitional care, and 36 % on the ward. Subgroup analysis revealed specific drug-related problem patterns for each clinical department. The number of drug-related problems was found to be associated with the number of drugs and age. CONCLUSION: Drug-related problems frequently occur in all investigated clinical departments. A holistic pharmaceutical care service could be an option to address this issue. In case of limited resources, individual drug-related problem patterns can be used as a basis for a tailored pharmaceutical care service. As number of drugs and age have been shown to be significant risk factors, it is crucial that the healthcare team including the pharmacist pays special attention to elderly patients and those with polymedication.

A Modeling and Simulation Framework for Adverse Events in Erlotinib-Treated Non-Small-Cell Lung Cancer Patients.

Treatment with erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor used for treating non-small-cell lung cancer (NSCLC) and other cancers, is frequently associated with adverse events (AE). We present a modeling and simulation framework for the most common erlotinib-induced AE, rash, and diarrhea, providing insights into erlotinib toxicity. We used the framework to investigate the safety of high-dose erlotinib pulses proposed to limit acquired resistance while treating NSCLC. Continuous-time Markov models were developed using rash and diarrhea AE data from 39 NSCLC patients treated with erlotinib (150 mg/day). Exposure and different covariates were investigated as predictors of variability. Rash was also tested as a survival predictor. Models developed were used in a simulation analysis to compare the toxicities of different regimens, including the previously mentioned pulsed strategy. Probabilities of experiencing rash or diarrhea were found to be highest early during treatment. Rash, but not diarrhea, was positively correlated with erlotinib exposure. In contrast with some common understandings, radiotherapy decreased transitioning to higher rash grades by 81% (p < 0.01), and experiencing rash was not correlated with positive survival outcomes. Model simulations predicted that the proposed pulsed regimen (1600 mg/week + 50 mg/day remaining week days) results in a maximum of 20% of the patients suffering from severe rash throughout the treatment course in comparison to 12% when treated with standard dosing (150 mg/day). In conclusion, the framework demonstrated that radiotherapy attenuates erlotinib-induced rash, providing an opportunity to use radiotherapy and erlotinib together, and demonstrated the tolerability of high-dose pulses intended to address acquired resistance to erlotinib.

Task allocation in cancer medication management - integrating the pharmacist.

OBJECTIVE: This study was conducted to define the task allocation in multiprofessional cancer medication management (MCMM) with a special focus on the role of the pharmacist as well as patient education and counseling. The acceptance of the proposed task allocation and the perceptions on multiprofessional teamwork were explored on a national level. METHODS: We held local focus group meetings (University of Bonn with collaboration partners) to identify MCMM tasks. With the Delphi technique the tasks were allocated to physicians, pharmacists and nurses. Professionals (members of the German Cancer Society) were approached nationwide via an online questionnaire to evaluate the acceptance of the MCMM model and explore their perceptions on multiprofessional teamwork. RESULTS: The MCMM model comprised 38 tasks including 11 on patient education and counseling. It was rated to be reasonable (79%) and feasible (68%). Barriers and benefits of multiprofessional teamwork stated were patient-, team-, therapy-, structure-, and resources-related. CONCLUSIONS: The MCMM model integrates the pharmacist with responsibilities in patient education and counseling as well as prevention of drug-related problems. The approach was generally appreciated nationwide by the professions. PRACTICE IMPLICATIONS: The proposed model can serve as a tool to trigger changes in cancer medication management.

Assessment of urinary mephenytoin metrics to phenotype for CYP2C19 and CYP2B6 activity.

OBJECTIVES: (S)-Mephenytoin is selectively metabolised to (S)-4'-hydroxymephenytoin by CYP2C19. The urinary excretion of 4'-hydroxymephenytoin reflects the activity of individual enzymes. We evaluated fractioned urinary collection and beta-glucuronidase pre-treatment in order to determine the optimal CYP2C19 metrics. We also assessed whether urinary excretion of N-desmethylmephenytoin (nirvanol) might be a useful CYP2B6 metric in in vivo studies. METHODS: A 50-mg dose of mephenytoin was administered to 52 volunteers as a component of phenotyping cocktails in four separate studies. Urine was collected up to 166 h post-dose. Urinary excretion of 4'-hydroxymephenytoin and nirvanol was quantified by liquid chromatography-tandem mass spectrometry, and common CYP2C19 and CYP2B6 genotypes were determined. RESULTS: Cumulative excretion of 4'-hydroxymephenytoin in urine with beta-glucuronidase treatment collected from before mephenytoin administration up to 12-16 h thereafter showed the greatest difference between CYP2C19 genotypes and the lowest intra-individual variability (7%). Renal elimination of nirvanol was highest for a *4/*4 individual and lowest for individuals carrying the *5/*5 and *1/*7 genotype, but lasted for several weeks, thus making its use in cross-over studies difficult. CONCLUSION: Cumulative urinary excretion of 4'-hydroxymephenytoin 0-12 h post-administration is a sensitive and reproducible metric of CYP2C19 activity, enabling the effect of a drug on CYP2C19 to be assessed in a small sample size of n=6 volunteers. While nirvanol excretion may reflect CYP2B6 activity in vivo, it is not useful for CYP2B6 phenotyping.

Psychometric assessment and application of a questionnaire measuring patient: satisfaction with information on cancer treatment.

OBJECTIVE: Pharmaceutical care follows a needs-based approach. Cancer patients form a group with particular needs. Information about cancer treatment plays an important role in terms of coping strategies, initiation of self-care behaviour, and quality of life. In order to develop pharmaceutical care strategies for cancer patients, it is important to assess patients' information needs. This survey aims at providing a suitable instrument to measure patient satisfaction with information on cancer treatment and to reveal the present situation in Germany. METHODS: Since there was no suitable German measure available, the Canadian 'Patient Satisfaction with Cancer Treatment Education (PS-CaTE) questionnaire' was translated into German and its test quality criteria were examined. Selected socio-demographic variables were added to the original version of the questionnaire to facilitate subgroup analysis. A pre-test was performed to assess the reliability of the adapted instrument. The questionnaire was distributed among patients of cooperating hospitals, oncology practices, and self-aid groups over Germany. RESULTS: The pre-test established a good reliability of the instrument. In the main survey, overall satisfaction, on a 5-point Likert scale, showed a median score of 3.5, where 5 represented the highest degree of satisfaction. A subscale analysis revealed that satisfaction with information provided on adverse events and complementary treatment options was lower compared to the information provided on cancer treatment. A stepwise multiple-regression analysis identified three significant predictors of satisfaction: a) diagnosis of a mammary carcinoma; b) recent diagnosis; and c) treatment by a primary-care oncologist. Patients with a mammary carcinoma and patients treated by a primary-care oncologist were less satisfied, and patients with a recent diagnosis were more satisfied compared to other patients. In comparison to other information sources, pharmacists still seem to play a minor role as a source of information for patients. CONCLUSIONS: The version of the questionnaire with a total of 14 items seems to be suitable for measuring patient satisfaction with information. Additional research is needed to further verify the validity of the instrument. The questionnaire may help pharmaceutical-care providers to develop needs-based information strategies. The assessment of patient satisfaction can contribute to the outcome evaluation of pharmaceutical care. The fact that pharmacists are not yet being recognised by most patients as a source of information should support an intensified and more active offer of care by the pharmacist.

From oncology pharmacy to pharmaceutical care: new contributions to multidisciplinary cancer care.

In recent years a paradigm shift towards a patient-focused rather than a disease-focused approach occurred in many health care systems. The pharmacy profession experienced an accordant development. The traditional drug-oriented services expanded towards patient-oriented services. In oncology, pharmacists established central services for compounding of cytotoxic drugs and offered therapeutic drug monitoring for critical substances. Pharmaceutical care concepts are now being introduced to optimize individual drug therapy. Pharmaceutical care aims at improving safety and therapeutic outcomes and consequently, the patient's quality of life. These objectives imply a close relationship to supportive care. To achieve this, a multidisciplinary approach seems to be beneficial.