We have described the influence of weight, renal function, age and plasma protein binding on the pharmacokinetics of linezolid. This combined pharmacokinetic, pharmacodynamic and turnover model identified that the most common mechanism of thrombocytopenia associated with linezolid is PDI. Impaired RF increases thrombocytopenia by a pharmacokinetic mechanism. The linezolid dose should be reduced in RF.

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Using the urinary 8-hydroxydeoxyguanosine (8-OHdG) concentration, effects of participation in a two-day ultramarathon race period on oxidative DNA damage were investigated in Japanese nonprofessional runners. Before the first day (baseline), after the first day (mid-race) of 40-km running, and after the second day (post-race) of 90 km running, biomaterials were successfully sampled from 95 participants (males, 79; females, 16) who completed the full race. We analyzed urine for 8-OHdG and blood for aspartate aminotransferase (AST), creatine phosphokinase (CPK) and myoglobin, and evaluated fluctuation in the values at three sampling time points. Adjusted baseline urinary 8-OHdG levels (microg/g creatinine) (mean +/- standard deviation) showed no significant differences between males and females, at 2.85 +/- 1.17 and 3.04 +/- 1.56, respectively. In males, mid-race urinary 8-OHdG levels rose to 3.29 +/- 1.15 (p < 0.01), but then returned to 2.73 +/- 1.16 at the post-race time point (p < 0.01). In females, a similar increase to 3.32 +/- 1.47 and subsequent decline to 2.80 +/- 1.47 were noted. In contrast, AST, CPK and myoglobin were increased at both mid- and post-time points and particularly the latter, independent of the sex. Extreme prolonged exercise in a two-day ultramarathon race period causes oxidative DNA damage but antioxidant repair systems are apparently induced to protect against oxidative DNA stress with physical exercise.

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Postmarketing surveillance is useful to collect safety data in real‐world clinical settings. In this study, we applied postmarketing real‐world data on a mechanistic model analysis for neutropenic profiles of eribulin in patients with recurrent or metastatic breast cancer. Demographic and safety data were collected using an active surveillance method from eribulin‐treated recurrent or metastatic breast cancer patients. Changes in neutrophil counts over time were analyzed using a mechanistic pharmacodynamic model. Pathophysiological factors that might affect the severity of neutropenia were investigated, and neutropenic patterns were simulated for different treatment schedules. Clinical and laboratory data were collected from 401 patients (5199 neutrophil count measurements) who had not received granulocyte colony‐stimulating factor and were eligible for pharmacodynamic analysis. The estimated mean parameters were as follows: mean transit time = 104.5 h, neutrophil proliferation rate constant = 0.0377 h−1, neutrophil elimination rate constant = 0.0295 h−1, and linear coefficient of drug effect = 0.0413 mL/ng. Low serum albumin levels and low baseline neutrophil counts were associated with severe neutropenia. The probability of grade ≥3 neutropenia was predicted to be 69%, 27%, and 27% for patients on standard, biweekly, and triweekly treatment scenarios, respectively, based on virtual simulations using the developed pharmacodynamic model. In conclusion, this is the first application of postmarketing surveillance data to a model‐based safety analysis. This analysis of safety data reflecting authentic clinical settings will provide useful information on the safe use and potential risk factors of eribulin.

SummaryAnnual intravenous administration of zoledronic acid is used in the treatment of osteoporosis. A mathematical model was developed to predict bone mineral density up to 2 years after two annual doses of zoledronic acid from the early values of a bone resorption marker in osteoporosis patients.IntroductionThe measurement of bone mineral density (BMD) has been used as a surrogate marker instead of the observation of incident fractures to detect the efficacy of treatment. However, this method requires a long time to obtain significant changes. On the other hand, bone resorption markers respond to bone resorption inhibitors within a few weeks. Therefore, the aim of this study was to develop a mathematical model predicting long-term BMD after two annual doses of zoledronic acid (ZOL) using the early response of a bone resorption marker in osteoporosis patients.MethodsThe model was constructed using 3410 tartrate-resistant acid phosphatase 5b (TRACP-5b) serum concentrations and 1146 lumbar spine (L2-L4) BMD values from 306 patients with primary osteoporosis. A mathematical model was developed to describe the time-dependent profiles of TRACP-5b and BMD.ResultsThe percentage changes from baseline of the BMD (%BMD) at up to 2 years were predicted from patients’ baseline BMD and baseline and 12-week TRACP-5b values by the model obtained. The simulated 90% prediction interval almost covered the observed %BMD distribution at each time point, and the predictions were comparable to the observed %BMD.ConclusionsThis is the first model to predict BMD for up to 2 years following two annual doses of ZOL using patients’ background characteristics and the early response of TRACP-5b. This model allows us to inform patients at the initial stage of ZOL treatment of their predicted response to treatment.Electronic supplementary materialThe online version of this article (10.1007/s00198-018-4376-1) contains supplementary material, which is available to authorized users.

Background: Potential novel strategies for adverse event (AE) management of osimertinib therapy, including therapeutic drug monitoring and the use of biomarkers, have not yet been fully investigated. This study aimed to evaluate (1) the relationship between exposure to osimertinib, especially its active metabolites (AZ5104 and AZ7550), and AEs, and (2) the relationship between germline polymorphisms and AEs. Methods: We conducted a prospective, longitudinal observational study of 53 patients with advanced non-small cell lung cancer receiving osimertinib therapy from February 2019 to April 2022. A population pharmacokinetic model was developed to estimate the area under the serum concentration–time curve from 0 to 24 h (AUC0–24) of osimertinib and its metabolites. Germline polymorphisms were analyzed using TaqMan® SNP genotyping and CycleavePCR® assays. Results: There was a significant association between the AUC0–24 of AZ7550 and grade ≥ 2 paronychia (p = 0.043) or anorexia (p = 0.011) and between that of osimertinib or AZ5104 and grade ≥ 2 diarrhea (p = 0.026 and p = 0.049, respectively). Furthermore, the AUC0–24 of AZ5104 was significantly associated with any grade ≥ 2 AEs (p = 0.046). EGFR rs2293348 and rs4947492 were associated with severe AEs (p = 0.019 and p = 0.050, respectively), and ABCG2 rs2231137 and ABCB1 rs1128503 were associated with grade ≥ 2 AEs (p = 0.008 and p = 0.038, respectively). Conclusion: Higher exposures to osimertinib, AZ5104, and AZ7550 and polymorphisms in EGFR, ABCG2, and ABCB1 were related to higher severity of AEs; therefore, monitoring these may be beneficial for osimertinib AE management.