Clinical Pharmacokinetics最新文献

{"title":"Tacrolimus Variability and Clinical Outcomes in the Early Post-lung Transplantation Period: Oral Versus Continuous Intravenous Administration","authors":"","doi":"10.1007/s40262-024-01368-1","DOIUrl":"https://doi.org/10.1007/s40262-024-01368-1","url":null,"abstract":"<h3>Abstract</h3> <span> <h3>Background and Objective</h3> <p>High variability in tacrolimus pharmacokinetics directly after lung transplantation (LuTx) may increase the risk for acute kidney injury (AKI) and transplant rejection. The primary objective was to compare pharmacokinetic variability in patients receiving tacrolimus orally versus intravenously early after LuTx.</p> </span> <span> <h3>Methods</h3> <p>Pharmacokinetic and clinical data from 522 LuTx patients transplanted between 2010 and 2020 in two university hospitals were collected to compare orally administered tacrolimus to intravenous tacrolimus early post-transplantation. Tacrolimus blood concentration variability, measured as intrapatient variability (IPV%) and percentage of time within the therapeutic range (TTR%), was analyzed within the first 14 days after LuTx. Secondary outcomes were AKI, acute rejection, length of stay in the intensive care unit (ICU), and mortality in the ICU and during hospital admission.</p> </span> <span> <h3>Results</h3> <p>We included 224 patients in the oral and 298 in the intravenous group. The mean adjusted IPV% was 10.8% (95% confidence interval [CI] 6.9–14.6; <em>p</em> &lt; 0.001) higher in the oral group (27.2%) than the intravenous group (16.4%). The mean TTR% was 7.3% (95% CI − 11.3 to − 3.4; <em>p</em> &lt; 0.001) lower in the oral group (39.6%) than in the intravenous group (46.9%). The incidence of AKI was 46.0% for oral and 42.6% for intravenous administration (adjusted odds ratio [OR] 1.2; 95% CI 0.8–1.8; <em>p</em> = 0.451). The frequencies of clinically diagnosed acute rejection in the oral and intravenous groups were nonsignificant (24.6% vs 17.8%; OR 1.5 [95% CI 1.0–2.3; <em>p</em> = 0.059]). ICU and hospital mortality rate and ICU length of stay were similar.</p> </span> <span> <h3>Conclusions</h3> <p>Administering tacrolimus orally directly after LuTx leads to a higher variability in blood concentrations compared to intravenous administration. There was no difference in the occurrence of AKI or transplant rejection.</p> </span>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":"27 1","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140593706","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population Pharmacokinetics of Sacituzumab Govitecan in Patients with Metastatic Triple-Negative Breast Cancer and Other Solid Tumors","authors":"Abhishek G. Sathe, Indrajeet Singh, Pratap Singh, Paul M. Diderichsen, Xiaohui Wang, Peter Chang, Atiya Taqui, See Phan, Sandhya Girish, Ahmed A. Othman","doi":"10.1007/s40262-024-01366-3","DOIUrl":"https://doi.org/10.1007/s40262-024-01366-3","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background and Objective</h3><p>Sacituzumab govitecan (SG) is an antibody–drug conjugate composed of an antibody with affinity for Trop-2 coupled to SN-38 via hydrolyzable linker. SG is approved for patients with metastatic triple-negative breast cancer (mTNBC) who have received two or more prior chemotherapies (at least one in a metastatic setting) and for patients with pretreated hormone receptor positive (HR+)/human epidermal growth factor receptor 2 negative (HER2–) metastatic breast cancer.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>In these analyses, the pharmacokinetics of SG, free SN-38, and total antibody (tAB) were characterized using data from 529 patients with mTNBC or other solid tumors across two large clinical trials (NCT01631552; ASCENT, NCT02574455). Three population pharmacokinetic models were constructed using non-linear mixed-effects modeling; clinically relevant covariates were evaluated to assess their impact on exposure. Models for SG and tAB were developed independently whereas free SN-38 was sequentially generated via a first-order release process from SG.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Pharmacokinetics of the three analytes were each described by a two-compartment model with estimated body weight-based scaling exponents for clearance and volume. Typical parameter estimates for clearance and steady-state volume of distribution were 0.133 L/h and 3.68 L for SG and 0.0164 L/h and 4.26 L for tAB, respectively. Mild-to-moderate renal impairment, mild hepatic impairment, age, sex, baseline albumin level, tumor type, <i>UGT1A1</i> genotype, or Trop-2 expression did not have a clinically relevant impact on exposure for any of the three analytes.</p><h3 data-test=\"abstract-sub-heading\">Conclusions</h3><p>These analyses support the approved SG dosing regimen of 10 mg/kg as intravenous infusion on days 1 and 8 of 21-day cycles and did not identify a need for dose adjustment based on evaluated covariates or disease characteristics.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":"6 1","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140593610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Relative Bioavailability of Dolutegravir (DTG) and Emtricitabine/Tenofovir Alafenamide Fumarate (F/TAF) Administered as Paediatric Tablet Formulations in Healthy Volunteers","authors":"Lisanne A. H. Bevers, Anne E. M. Kamphuis, L. C. Wendy van der Wekken-Pas, Rory Leisegang, David M. Burger, Angela Colbers","doi":"10.1007/s40262-024-01365-4","DOIUrl":"https://doi.org/10.1007/s40262-024-01365-4","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background and objective</h3><p>Within the UNIVERSAL project (RIA2019PD-2882) we aim to develop a paediatric dolutegravir (DTG)/emtricitabine (FTC or F)/tenofovir alafenamide (TAF) fixed-dose combination. To inform dosing of this study, we undertook a relative bioavailability (RBA) study in healthy volunteers to investigate a potential pharmacokinetic effect when paediatric formulations of DTG and F/TAF are taken together.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>Participants received all of the following treatments as paediatric formulations in randomised order: a single dose of 180/22.5 mg F/TAF; a single dose of 30 mg DTG; a single dose of 180/22.5 mg F/TAF plus 30 mg DTG. Blood concentrations of DTG, FTC, TAF, and tenofovir (TFV) were measured over 48 h post-dose. If the 90% confidence intervals (CIs) of the geometric least squares mean (GLSM) ratios of area under the curve (AUC) and maximum concentration (<i>C</i>_max) of each compound were within 0.70–1.43, we considered this as no clinically relevant PK interaction.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>A total of 15 healthy volunteers were included. We did not observe a clinically relevant PK interaction between the paediatric DTG and F/TAF formulations for the compounds DTG, FTC, and TFV. For TAF, the lower boundaries of the 90% CIs of the GLSM ratios of the AUC_0–∞ and <i>C</i>_max fell outside our acceptance criteria of 0.70–1.43.</p><h3 data-test=\"abstract-sub-heading\">Conclusions</h3><p>Although TAF AUC and <i>C</i>_max 90% CIs fell outside the pre-defined criteria (0.62–1.11 and 0.65–1.01, respectively), no consistent effect on TAF PK was observed, likely due to high inter-subject variability. Moreover, there are several reasons to rely on TFV exposure as being more clinically relevant than TAF exposure. Therefore, we found no clinically relevant interactions in this study.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":"32 1","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140593710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dosing of Convalescent Plasma and Hyperimmune Anti-SARS-CoV-2 Immunoglobulins: A Phase I/II Dose-Finding Study.","authors":"Sammy Huygens, Tim Preijers, Francis H Swaneveld, Ilona Kleine Budde, Corine H GeurtsvanKessel, Birgit C P Koch, Bart J A Rijnders","doi":"10.1007/s40262-024-01351-w","DOIUrl":"10.1007/s40262-024-01351-w","url":null,"abstract":"<p><strong>Background and objective: </strong>During the COVID-19 pandemic, trials on convalescent plasma (ConvP) were performed without preceding dose-finding studies. This study aimed to assess potential protective dosing regimens by constructing a population pharmacokinetic (popPK) model describing anti-SARS-CoV-2 antibody titers following the administration of ConvP or hyperimmune globulins (COVIg).</p><p><strong>Methods: </strong>Immunocompromised patients, testing negative for anti-SARS-CoV-2 spike antibodies despite vaccination, received a range of anti-SARS-CoV-2 antibodies in the form of COVIg or ConvP infusion. The popPK analysis was performed using NONMEM v7.4. Monte Carlo simulations were performed to assess potential COVIg and ConvP dosing regimens for prevention of COVID-19.</p><p><strong>Results: </strong>Forty-four patients were enrolled, and data from 42 were used for constructing the popPK model. A two-compartment elimination model with mixed residual error best described the Nab-titers after administration. Inter-individual variation was associated to CL (44.3%), V1 (27.3%), and V2 (29.2%). Lean body weight and type of treatment (ConvP/COVIg) were associated with V1 and V2, respectively. Median elimination half-life was 20 days (interquartile range: 17-25 days). Simulations demonstrated that even monthly infusions of 600 mL of the ConvP or COVIg used in this trial would not achieve potentially protective serum antibody titers for > 90% of the time. However, as a result of hybrid immunity and/or repeated vaccination, plasma donors with extremely high antibody titers are now readily available, and a > 90% target attainment should be possible.</p><p><strong>Conclusion: </strong>The results of this study may inform future intervention studies on the prophylactic and therapeutic use of antiviral antibodies in the form of ConvP or COVIg.</p><p><strong>Clinical trial registration number: </strong>NL9379 (The Netherlands Trial Register).</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"497-509"},"PeriodicalIF":4.5,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11052786/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139995797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Pharmacokinetics and Pharmacodynamics of Naloxone.","authors":"Teijo I Saari, John Strang, Ola Dale","doi":"10.1007/s40262-024-01355-6","DOIUrl":"10.1007/s40262-024-01355-6","url":null,"abstract":"<p><p>Naloxone is a World Health Organization (WHO)-listed essential medicine and is the first choice for treating the respiratory depression of opioids, also by lay-people witnessing an opioid overdose. Naloxone acts by competitive displacement of opioid agonists at the μ-opioid receptor (MOR). Its effect depends on pharmacological characteristics of the opioid agonist, such as dissociation rate from the MOR receptor and constitution of the victim. Aim of treatment is a balancing act between restoration of respiration (not consciousness) and avoidance of withdrawal, achieved by titration to response after initial doses of 0.4-2 mg. Naloxone is rapidly eliminated [half-life (t_1/2) 60-120 min] due to high clearance. Metabolites are inactive. Major routes for administration are intravenous, intramuscular, and intranasal, the latter primarily for take-home naloxone. Nasal bioavailability is about 50%. Nasal uptake [mean time to maximum concentration (T_max) 15-30 min] is likely slower than intramuscular, as reversal of respiration lag behind intramuscular naloxone in overdose victims. The intraindividual, interindividual and between-study variability in pharmacokinetics in volunteers are large. Variability in the target population is unknown. The duration of action of 1 mg intravenous (IV) is 2 h, possibly longer by intramuscular and intranasal administration. Initial parenteral doses of 0.4-0.8 mg are usually sufficient to restore breathing after heroin overdose. Fentanyl overdoses likely require higher doses of naloxone. Controlled clinical trials are feasible in opioid overdose but are absent in cohorts with synthetic opioids. Modeling studies provide valuable insight in pharmacotherapy but cannot replace clinical trials. Laypeople should always have access to at least two dose kits for their interim intervention.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"397-422"},"PeriodicalIF":4.5,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11052794/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140130933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optimization of Ganciclovir and Valganciclovir Starting Dose in Children by Machine Learning.","authors":"Laure Ponthier, Julie Autmizguine, Benedicte Franck, Anders Åsberg, Philippe Ovetchkine, Alexandre Destere, Pierre Marquet, Marc Labriffe, Jean-Baptiste Woillard","doi":"10.1007/s40262-024-01362-7","DOIUrl":"10.1007/s40262-024-01362-7","url":null,"abstract":"<p><strong>Background and objectives: </strong>Ganciclovir (GCV) and valganciclovir (VGCV) show large interindividual pharmacokinetic variability, particularly in children. The objectives of this study were (1) to develop machine learning (ML) algorithms trained on simulated pharmacokinetics profiles obtained by Monte Carlo simulations to estimate the best ganciclovir or valganciclovir starting dose in children and (2) to compare its performances on real-world profiles to previously published equation derived from literature population pharmacokinetic (POPPK) models achieving about 20% of profiles within the target.</p><p><strong>Materials and methods: </strong>The pharmacokinetic parameters of four literature POPPK models in addition to the World Health Organization (WHO) growth curve for children were used in the mrgsolve R package to simulate 10,800 pharmacokinetic profiles. ML algorithms were developed and benchmarked to predict the probability to reach the steady-state, area-under-the-curve target (AUC_0-24 within 40-60 mg × h/L) based on demographic characteristics only. The best ML algorithm was then used to calculate the starting dose maximizing the target attainment. Performances were evaluated for ML and literature formula in a test set and in an external set of 32 and 31 actual patients (GCV and VGCV, respectively).</p><p><strong>Results: </strong>A combination of Xgboost, neural network, and random forest algorithms yielded the best performances and highest target attainment in the test set (36.8% for GCV and 35.3% for the VGCV). In actual patients, the best GCV ML starting dose yielded the highest target attainment rate (25.8%) and performed equally for VGCV with the Franck model formula (35.3% for both).</p><p><strong>Conclusion: </strong>The ML algorithms exhibit good performances in comparison with previously validated models and should be evaluated prospectively.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"539-550"},"PeriodicalIF":4.5,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140139989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population Pharmacodynamic Dose-Response Analysis of Serum Potassium Following Dosing with Sodium Zirconium Cyclosilicate.","authors":"Robert C Penland, Magnus Åstrand, David W Boulton, Mats Någård","doi":"10.1007/s40262-024-01360-9","DOIUrl":"10.1007/s40262-024-01360-9","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Sodium zirconium cyclosilicate (SZC) is an approved oral treatment for hyperkalemia that selectively binds potassium (K&lt;sup&gt;+&lt;/sup&gt;) in the gastrointestinal tract and removes K&lt;sup&gt;+&lt;/sup&gt; from the body through increased fecal excretion. Here, we describe the population pharmacodynamic (PopPD) response of serum K&lt;sup&gt;+&lt;/sup&gt; concentration in patients with hyperkalemia who are treated with SZC, estimate the impact of patients' intrinsic and extrinsic factors, and compare predicted serum K&lt;sup&gt;+&lt;/sup&gt; responses between 5 g alternate daily (QOD) and 2.5 g once daily (QD) maintenance doses.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;PopPD analysis was based on pooled data from seven phase II and III clinical trials for SZC. A semi-mechanistic longitudinal mixed-effects (base) model was used to characterize serum K&lt;sup&gt;+&lt;/sup&gt; concentration after SZC dosing. Indirect-response, virtual pharmacokinetics-pharmacodynamics (PK-PD) modeling was used to mimic the drug exposure compartment. Full covariate modeling was used to assess covariate impact on the half-maximal effective concentration of drug (EC&lt;sub&gt;50&lt;/sub&gt;), placebo response, and K&lt;sub&gt;out&lt;/sub&gt;. Models were evaluated using goodness-of-fit plots, relative standard errors, and visual predictive checks, and data were stratified to optimize model performance across subgroups. Covariate effects were evaluated based on the magnitude of change in serum K&lt;sup&gt;+&lt;/sup&gt; between baseline and end of correction phase dosing (48 h, SZC 10 g three times a day) and maintenance phase dosing (28 days, SZC 10 g QD) using a reference subject.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;The analysis data set included 2369 patients and 25,764 serum K&lt;sup&gt;+&lt;/sup&gt; observations. The mean (standard deviation) patient age was 66.0 (12) years, 61% were male, 68% were White, 34% had congestive heart failure, and 62% had diabetes. Mean (standard deviation) serum K&lt;sup&gt;+&lt;/sup&gt; at baseline was 5.49 (0.43) mmol/L. Both the base and full covariance models adequately described observed data. In the final model, there was a sigmoid exposure response on K&lt;sub&gt;in&lt;/sub&gt;, with EC&lt;sub&gt;50&lt;/sub&gt; of 32.8 g and a Hill coefficient of 1.36. The predicted placebo-adjusted dose-responses of serum K&lt;sup&gt;+&lt;/sup&gt; change appeared nearly linear in the correction and maintenance phases. No clinically meaningful difference in placebo-adjusted serum K&lt;sup&gt;+&lt;/sup&gt; change from baseline at 28 days was observed between maintenance regimens of SZC 5 g QOD and 2.5 g QD. A greater SZC treatment response was associated with high serum K&lt;sup&gt;+&lt;/sup&gt; at baseline, advanced age, lower body weight, lower estimated glomerular filtration rate, and Black/African American and Asian race, compared with the reference patient. The impact of heart failure status and diabetes status was only minor.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;The PopPD model of SZC adequately described changes in serum K&lt;sup&gt;+&lt;/sup&gt; concentration during correction and maintenance phase dosing","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"551-560"},"PeriodicalIF":4.5,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11052801/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140174029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Demonstrating Bioequivalence for Two Dose Strengths of Niraparib and Abiraterone Acetate Dual-Action Tablets Versus Single Agents: Utility of Clinical Study Data Supplemented with Modeling and Simulation.","authors":"Alex Yu, Anasuya Hazra, James Juhui Jiao, Peter Hellemans, Anna Mitselos, Hui Tian, Juan Jose Perez Ruixo, Nahor Haddish-Berhane, Daniele Ouellet, Alberto Russu","doi":"10.1007/s40262-023-01340-5","DOIUrl":"10.1007/s40262-023-01340-5","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background and objective: &lt;/strong&gt;The combination of niraparib and abiraterone acetate (AA) plus prednisone is under investigation for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) and metastatic castration-sensitive prostate cancer (mCSPC). Regular-strength (RS) and lower-strength (LS) dual-action tablets (DATs), comprising niraparib 100 mg/AA 500 mg and niraparib 50 mg/AA 500 mg, respectively, were developed to reduce pill burden and improve patient experience. A bioequivalence (BE)/bioavailability (BA) study was conducted under modified fasting conditions in patients with mCRPC to support approval of the DATs.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;This open-label randomized BA/BE study (NCT04577833) was conducted at 14 sites in the USA and Europe. The study had a sequential design, including a 21-day screening phase, a pharmacokinetic (PK) assessment phase comprising three periods [namely (1) single-dose with up to 1-week run-in, (2) daily dose on days 1-11, and (3) daily dose on days 12-22], an extension where both niraparib and AA as single-agent combination (SAC; reference) or AA alone was continued from day 23 until discontinuation, and a 30-day follow-up phase. Patients were randomly assigned in a parallel-group design (four-sequence randomization) to receive a single oral dose of niraparib 100 mg/AA 1000 mg as a LS-DAT or SAC in period 1, and patients continued as randomized into a two-way crossover design during periods 2 and 3 where they received niraparib 200 mg/AA 1000 mg once daily as a RS-DAT or SAC. The design was powered on the basis of crossover assessment of RS-DAT versus SAC. During repeated dosing (periods 2 and 3, and extension phase), all patients also received prednisone/prednisolone 5 mg twice daily. Plasma samples were collected for measurement of niraparib and abiraterone plasma concentrations. Statistical assessment of the RS-DAT and LS-DAT versus SAC was performed on log-transformed pharmacokinetic parameters data from periods 2 and 3 (crossover) and from period 1 (parallel), respectively. Additional paired analyses and model-based bioequivalence assessments were conducted to evaluate the similarity between the LS-DAT and SAC.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;For the RS-DAT versus SAC, the 90% confidence intervals (CI) of geometric mean ratios (GMR) for maximum concentration at a steady state (C&lt;sub&gt;max,ss&lt;/sub&gt;) and area under the plasma concentration-time curve from 0-24 h at a steady state (AUC &lt;sub&gt;0-24h,ss&lt;/sub&gt;) were respectively 99.18-106.12% and 97.91-104.31% for niraparib and 87.59-106.69 and 86.91-100.23% for abiraterone. For the LS-DAT vs SAC, the 90% CI of GMR for AUC&lt;sub&gt;0-72h&lt;/sub&gt; of niraparib was 80.31-101.12% in primary analysis, the 90% CI of GMR for C&lt;sub&gt;max,ss&lt;/sub&gt; and AUC &lt;sub&gt;0-24h&lt;/sub&gt;,ss of abiraterone was 85.41-118.34% and 86.51-121.64% respectively, and 96.4% of simulated LS-DAT versus SAC BE trials met the BE criteria for both niraparib and ab","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"511-527"},"PeriodicalIF":4.5,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11052869/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140021122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Evaluation of the Effect of Encorafenib on Bupropion, Rosuvastatin, and Coproporphyrin I and Considerations for Statin Coadministration.","authors":"Joseph Piscitelli, Micaela B Reddy, Lance Wollenberg, Laurence Del Frari, Jason Gong, Linda Wood, Yizhong Zhang, Kyle Matschke, Jason H Williams","doi":"10.1007/s40262-024-01352-9","DOIUrl":"10.1007/s40262-024-01352-9","url":null,"abstract":"<p><strong>Background and objectives: </strong>Encorafenib is a kinase inhibitor indicated for the treatment of patients with unresectable or metastatic melanoma or metastatic colorectal cancer, respectively, with selected BRAF V600 mutations. A clinical drug-drug interaction (DDI) study was designed to evaluate the effect of encorafenib on rosuvastatin, a sensitive substrate of OATP1B1/3 and breast cancer resistance protein (BCRP), and bupropion, a sensitive CYP2B6 substrate. Coproporphyrin I (CP-I), an endogenous substrate for OATP1B1, was measured in a separate study to deconvolute the mechanism of transporter DDI.</p><p><strong>Methods: </strong>DDI study participants received a single oral dose of rosuvastatin (10 mg) and bupropion (75 mg) on days - 7, 1, and 14 and continuous doses of encorafenib (450 mg QD) and binimetinib (45 mg BID) starting on day 1. The CP-I data were collected from participants in a phase 3 study who received encorafenib (300 mg QD) and cetuximab (400 mg/m² initial dose, then 250 mg/m² QW). Pharmacokinetic and pharmacodynamic analysis was performed using noncompartmental and compartmental methods.</p><p><strong>Results: </strong>Bupropion exposure was not increased, whereas rosuvastatin C_max and area under the receiver operating characteristic curve (AUC) increased approximately 2.7 and 1.6-fold, respectively, following repeated doses of encorafenib and binimetinib. Increase in CP-I was minimal, suggesting that the primary effect of encorafenib on rosuvastatin is through BCRP. Categorization of statins on the basis of their metabolic and transporter profile suggests pravastatin would have the least potential for interaction when coadministered with encorafenib.</p><p><strong>Conclusion: </strong>The results from these clinical studies suggest that encorafenib does not cause clinically relevant CYP2B6 induction or inhibition but is an inhibitor of BCRP and may also inhibit OATP1B1/3 to a lesser extent. Based on these results, it may be necessary to consider switching statins or reducing statin dosage accordingly for coadministration with encorafenib.</p><p><strong>Clinical trial registration: </strong>ClinicalTrials.gov NCT03864042, registered 6 March 2019.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"483-496"},"PeriodicalIF":4.5,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11052825/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139995796","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Time Course of the Interaction Between Oral Short-Term Ritonavir Therapy with Three Factor Xa Inhibitors and the Activity of CYP2D6, CYP2C19, and CYP3A4 in Healthy Volunteers.","authors":"Brit S Rohr, Evelyn Krohmer, Kathrin I Foerster, Jürgen Burhenne, Martin Schulz, Antje Blank, Gerd Mikus, Walter E Haefeli","doi":"10.1007/s40262-024-01350-x","DOIUrl":"10.1007/s40262-024-01350-x","url":null,"abstract":"<p><strong>Background: </strong>We investigated the effect of a 5-day low-dose ritonavir therapy, as it is used in the treatment of COVID-19 with nirmatrelvir/ritonavir, on the pharmacokinetics of three factor Xa inhibitors (FXaI). Concurrently, the time course of the activities of the cytochromes P450 (CYP) 3A4, 2C19, and 2D6 was assessed.</p><p><strong>Methods: </strong>In an open-label, fixed sequence clinical trial, the effect and duration of a 5-day oral ritonavir (100 mg twice daily) treatment on the pharmacokinetics of three oral microdosed FXaI (rivaroxaban 25 µg, apixaban 25 µg, and edoxaban 50 µg) and microdosed probe drugs (midazolam 25 µg, yohimbine 50 µg, and omeprazole 100 µg) was evaluated in eight healthy volunteers. The plasma concentrations of all drugs were quantified using validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods and pharmacokinetics were analysed using non-compartmental analyses.</p><p><strong>Results: </strong>Ritonavir increased the exposure of apixaban, edoxaban, and rivaroxaban, but to a different extent the observed area under the plasma concentration-time curve (geometric mean ratio 1.29, 1.46, and 1.87, respectively). A strong CYP3A4 inhibition (geometric mean ratio > 10), a moderate CYP2C19 induction 2 days after ritonavir (0.64), and no alteration of CYP2D6 were observed. A CYP3A4 recovery half-life of 2.3 days was determined.</p><p><strong>Conclusion: </strong>This trial with three microdosed FXaI suggests that at most the rivaroxaban dose should be reduced during short-term ritonavir, and only in patients receiving high maintenance doses. Thorough time series analyses demonstrated differential effects on three different drug-metabolising enzymes over time with immediate profound inhibition of CYP3A4 and only slow recovery after discontinuation.</p><p><strong>Clinical trial registration: </strong>EudraCT number: 2021-006643-39.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"469-481"},"PeriodicalIF":4.5,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11052790/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139930365","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}