Aims
The objective of this study was to evaluate the effects of a strong cytochrome P450 family (CYP) 3A4 inhibitor (itraconazole) and inducer (carbamazepine) on the pharmacokinetics and safety of ...nirmatrelvir/ritonavir.
Methods
Pharmacokinetics were measured in two phase 1, open‐label, fixed‐sequence studies in healthy adults. During Period 1, oral nirmatrelvir/ritonavir 300 mg/100 mg twice daily was administered alone; during Period 2, it was administered with itraconazole or carbamazepine. Nirmatrelvir/ritonavir was administered as repeated doses or one dose in the itraconazole and carbamazepine studies, respectively. Nirmatrelvir and ritonavir plasma concentrations and adverse event (AE) rates in both periods were analysed.
Results
Each study included 12 participants. Following administration of nirmatrelvir/ritonavir with itraconazole (Test) or alone (Reference), test/reference ratios of the adjusted geometric means (90% CIs) for nirmatrelvir AUCtau and Cmax were 138.82% (129.25%, 149.11%) and 118.57% (112.50%, 124.97%), respectively. After administration of nirmatrelvir/ritonavir with carbamazepine (Test) or alone (Reference), test/reference ratios (90% CIs) of the adjusted geometric means for nirmatrelvir AUCinf and Cmax were 44.50% (33.77%, 58.65%) and 56.82% (47.04%, 68.62%), respectively. Nirmatrelvir/ritonavir was generally safe when administered with or without itraconazole or carbamazepine. No serious or severe AEs were reported.
Conclusions
Coadministration of a strong CYP3A4 inhibitor with a strong CYP3A inhibitor used for pharmacokinetic enhancement (i.e., ritonavir) resulted in small increases in plasma nirmatrelvir exposure, whereas coadministration of a strong inducer substantially decreased systemic nirmatrelvir and ritonavir exposures suggesting a contraindication in the label with CYP3A4 strong inducers. Administration of nirmatrelvir/ritonavir alone or with itraconazole or carbamazepine was generally safe.
Summary Background Inhibition of MEK stops cell proliferation and induces apoptosis; therefore, this enzyme is a key anticancer target. Trametinib is a selective, orally administered MEK1/MEK2 ...inhibitor. We aimed to define the maximum tolerated dose and recommended phase 2 dose of trametinib and to assess its safety, pharmacokinetics, pharmacodynamics, and response rate in individuals with advanced solid tumours. Methods We undertook a multicentre phase 1 study in patients with advanced solid tumours and adequate organ function. The study was in three parts: dose escalation to define the maximum tolerated dose; identification of the recommended phase 2 dose; and assessment of pharmacodynamic changes. Intermittent and continuous dosing regimens were analysed. Blood samples and tumour biopsy specimens were taken to assess pharmacokinetic and pharmacodynamic changes. Adverse events were defined with common toxicity criteria, and tumour response was measured by Response Evaluation Criteria In Solid Tumors. This study is registered with ClinicalTrials.gov , number NCT00687622. Findings We enrolled 206 patients (median age 58·5 years, range 19–92). Dose-limiting toxic effects included rash (n=2), diarrhoea (n=1), and central serous retinopathy (n=2). The most common treatment-related adverse events were rash or dermatitis acneiform (n=165; 80%) and diarrhoea (87; 42%), most of which were grade 1 and 2. The maximum tolerated dose was 3 mg once daily and the recommended phase 2 dose was 2 mg a day. The effective half-life of trametinib was about 4 days. At the recommended phase 2 dose, the exposure profile of the drug showed low interpatient variability and a small peak:trough ratio of 1·81. Furthermore, mean concentrations in plasma were greater than the preclinical target concentration throughout the dosing interval. Pathway inhibition and clinical activity were seen, with 21 (10%) objective responses recorded. Interpretation The recommended phase 2 dose of 2 mg trametinib once a day is tolerable, with manageable side-effects. Trametinib's inhibition of the expected target and clinical activity warrants its further development as a monotherapy and in combination. Funding GlaxoSmithKline.
To evaluate pharmacokinetics (PK) and safety after coadministration of nirmatrelvir/ritonavir or ritonavir alone with midazolam (a cytochrome P450 3A4 substrate) and dabigatran (a P-glycoprotein ...substrate).
PK was studied in 2 phase 1, open-label, fixed-sequence studies in healthy adults. Single oral doses of midazolam 2 mg (n = 12) or dabigatran 75 mg (n = 24) were administered alone and after steady state (i.e. ≥2 days) of nirmatrelvir/ritonavir 300 mg/100 mg and ritonavir 100 mg. Midazolam and dabigatran plasma concentrations and adverse events were analysed for each treatment.
After administration of midazolam with nirmatrelvir/ritonavir (test) or alone (reference), midazolam geometric mean area under the concentration-time curve extrapolated to infinity (AUC
) and maximum plasma concentration (C
) increased 14.3-fold and 3.7-fold, respectively. Midazolam coadministered with ritonavir (test) or alone (reference) resulted in 16.5-fold and 3.9-fold increases in midazolam geometric mean AUC
and C
, respectively. After administration of dabigatran with nirmatrelvir/ritonavir (test) or alone (reference), dabigatran geometric mean AUC
and C
increased 1.9-fold and 2.3-fold, respectively. Dabigatran coadministered with ritonavir (test) or alone (reference) resulted in a 1.7-fold increase in dabigatran geometric mean AUC
and C
. Midazolam or dabigatran exposures were generally comparable when coadministered with nirmatrelvir/ritonavir or ritonavir alone, with a slightly higher dabigatran C
with nirmatrelvir/ritonavir vs. ritonavir alone. Nirmatrelvir/ritonavir was generally safe when administered with or without midazolam or dabigatran. No serious or severe adverse events were reported.
Coadministration of midazolam or dabigatran with nirmatrelvir/ritonavir increased systemic exposure of midazolam or dabigatran. Midazolam exposures were comparable when coadministered with nirmatrelvir/ritonavir or ritonavir alone, suggesting no incremental effect of nirmatrelvir. Dabigatran C
was slightly higher when coadministered with nirmatrelvir/ritonavir compared with of ritonavir alone, suggesting a minor incremental effect of nirmatrelvir.
Nirmatrelvir is a potent and selective inhibitor of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease that is used as an oral antiviral coronavirus disease 2019 ...(COVID-19) treatment. To sustain unbound systemic trough concentrations above the antiviral in vitro 90% effective concentration value (EC
90
), nirmatrelvir is coadministered with 100 mg of ritonavir, a pharmacokinetic enhancer. Ritonavir inhibits nirmatrelvir’s cytochrome P450 (CYP) 3A4-mediated metabolism which results in renal elimination becoming the primary route of nirmatrelvir elimination when dosed concomitantly. Nirmatrelvir exhibits absorption-limited nonlinear pharmacokinetics. When coadministered with ritonavir in patients with mild-to-moderate COVID-19, nirmatrelvir reaches a maximum concentration of 3.43 µg/mL (11.7× EC
90
) in approximately 3 h on day 5 of dosing, with a geometric mean day 5 trough concentration of 1.57 µg/mL (5.4× EC
90
). Drug interactions with nirmatrelvir/ritonavir (PAXLOVID
TM
) are primarily attributed to ritonavir-mediated CYP3A4 inhibition, and to a lesser extent CYP2D6 and P-glycoprotein inhibition. Population pharmacokinetics and quantitative systems pharmacology modeling support twice daily dosing of 300 mg/100 mg nirmatrelvir/ritonavir for 5 days, with a reduced 150 mg/100 mg dose for patients with moderate renal impairment. Rapid clinical development of nirmatrelvir/ritonavir in response to the emerging COVID-19 pandemic was enabled by innovations in clinical pharmacology research, including an adaptive phase 1 trial design allowing direct to pivotal phase 3 development, fluorine nuclear magnetic resonance spectroscopy to delineate absorption, distribution, metabolism, and excretion profiles, and innovative applications of model-informed drug development to accelerate development.
Nirmatrelvir is a potent and selective severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) main protease inhibitor. Nirmatrelvir co‐packaged with ritonavir (as PAXLOVID) received US Food and ...Drug Administration (FDA) Emergency Use Authorization (EUA) on December 22, 2021, as an oral treatment for coronavirus disease 2019 (COVID‐19) and subsequent new drug application approval on May 25, 2023. Pharmacokinetic (PK) capillary blood sampling at‐home using Tasso‐M20 micro‐volumetric sampling device was implemented in the program, including three phase II/III outpatient and several clinical pharmacology studies supporting the EUA. The at‐home sampling complemented venous blood sampling procedures to enrich the PK dataset, to decrease the need for patients' site visit for PK sampling, and to allow different sampling approaches for flexibility and convenience. To demonstrate concordance/equivalence, bridging between venous plasma and Tasso dried blood results was conducted by comparing concentrations and derived PK parameters from both sampling approaches. In addition, a two‐compartment population PK model was utilized to bridge the plasma and Tasso data by estimating the PK parameters using blood‐to‐plasma ratio as a slope parameter. Operational challenges were successfully managed to implement at‐home PK sampling in global phase II/III trials. Sample quality was generally very good with less than 3% samples deemed as “not usable” from over 800 samples collected in all the studies. Experience gained from sites and patients will guide future broader implementations.
Deutetrabenazine (Austedo, Teva Pharmaceuticals) is a deuterated form of tetrabenazine. It is the first deuterated drug to receive US regulatory approval and is approved for treatment of chorea in ...Huntington’s disease and tardive dyskinesia. Two oral single dose studies comparing deutetrabenazine (25 mg) with tetrabenazine (25 mg) in healthy volunteers evaluated the impact of deuteration on pharmacokinetics of the active metabolites, alpha‐dihydrotetrabenazine (α‐HTBZ) and beta‐dihydrotetrabenazine (β‐HTBZ), metabolite profile, safety, and tolerability. In the two‐way, cross‐over study, the mean elimination half‐life of deuterated total (α + β)‐HTBZ was doubled compared with nondeuterated total (α + β)‐HTBZ, with a twofold increase in overall mean exposure (area under the concentration‐time curve from zero to infinity (AUC0–inf)) and a marginal increase in mean peak plasma concentration (Cmax). In the mass balance and metabolite profiling study, there were no novel plasma or urinary metabolites of 14C‐deutetrabenazine relative to 14C‐tetrabenazine. Specific deuteration in deutetrabenazine resulted in a superior pharmacokinetic profile and an increased ratio of active‐to‐inactive metabolites, attributes considered to provide significant benefits to patients.
This phase I/II single-arm study evaluated the safety, pharmacokinetics, pharmacodynamics, and activity of foretinib, an oral multikinase inhibitor of MET, ROS, RON, AXL, TIE-2, and VEGFR2, in the ...first-line setting in advanced hepatocellular carcinoma patients.
In the phase I part, advanced hepatocellular carcinoma patients were dose escalated on foretinib (30-60 mg) every day using the standard 3+3 design. Once the maximum tolerated dose (MTD) was determined, an additional 32 patients were dosed at the MTD in the phase II expansion cohort for assessment of efficacy and safety. Exploratory analyses were conducted to assess potential biomarkers that might correlate with clinical efficacy and survival.
The MTD of foretinib was established as 30 mg every day. The most frequent adverse events were hypertension, decreased appetite, ascites, and pyrexia. When dosed at 30 mg every day in the first-line setting, foretinib demonstrated promising antitumor activity. According to the modified mRECIST, the objective response rate was 22.9%, the disease stabilization rate 82.9%, and the median duration of response 7.6 months. The median time to progression was 4.2 months and the median overall survival (OS) was 15.7 months. Fifteen candidate biomarkers whose levels in the circulation were significantly altered in response to foretinib treatment were elucidated. Multivariate analyses identified IL6 and IL8 as independent predictors of OS.
Foretinib demonstrated promising antitumor activity and good tolerability in the first-line setting in Asian advanced hepatocellular carcinoma patients. Baseline plasma levels of IL6 or IL8 might predict the response to foretinib.
.
Clinicians have limited accuracy in the prediction of patient survival. We assessed the accuracy of probabilistic clinician prediction of survival (CPS) and temporal CPS for advanced cancer patients ...admitted to our acute palliative care unit, and identified factors associated with CPS accuracy. Eight physicians and 20 nurses provided their estimation of survival on admission by (a) the temporal approach, “What is the approximate survival for this patient (in days)?” and (b) the probabilistic approach, “What is the approximate probability that this patient will be alive (0%–100%)?” for ≥24 hours, 48 hours, 1 week, 2 weeks, 1 month, 3 months, and 6 months. We also collected patient and clinician demographics. Among 151 patients, the median age was 58 years, 95 (63%) were female, and 138 (81%) had solid tumors. The median overall survival time was 12 days. The median temporal CPS was 14 days for physicians and 20 days for nurses. Physicians were more accurate than nurses. A higher accuracy of temporal physician CPS was associated with older patient age. Probabilistic CPS was significantly more accurate than temporal CPS for both physicians and nurses, although this analysis was limited by the different criteria for determining accuracy. With the probabilistic approach, nurses were significantly more accurate at predicting survival at 24 hours and 48 hours, whereas physicians were significantly more accurate at predicting survival at 6 months. The probabilistic approach was associated with high accuracy and has practical implications.
摘要
医务人员预测患者生存期的准确性有限。本作者评估了概率法和时间法的医务人员生存期预测（CPS）和时间法CPS对用于收入本院急性姑息治疗科的晚期癌症患者的准确，并确定与CPS准确性相关的因素。8位医生和20位护士采用以下方法于患者入院时估算其患者入院时生存期：①时间法，“该患者的近似生存期是多长（天数）？”②概率法，“该患者生存≥24小时、48小时、1周、2周、1个月、3个月和6个月的近似概率是多少（0%∼100%）？”本作者亦还收集了患者和医务人员的人口学资料特征。151例患者的中位年龄为58岁，其中95例（63%）为女性，138例（81%）患有实体瘤。中位总生存期12天。医生和护士估算的时间法中位CPS分别为14天和20天。医生的准确性高于护士。对于年龄较大的患者，医生提供的时间法CPS准确性较高。无论是医生还是护士，概率法CPS的准确性均高于时间法CPS，具有统计学意义，尽管该分析受限于衡量准确性的标准不同。采用概率法时，护士对24小时和48小时的生存概率的预测更准确，而医生对6个月时的生存概率的预测更准确，差异均具有统计学意义。概率法的准确性较高，具有实用价值。
The accuracy of probabilistic and temporal clinician prediction of survival for advanced cancer patients admitted to an acute palliative care unit were assessed and compared. Factors associated with prediction accuracy were identified.
Abstract Purpose This phase 1b study determined the safety, tolerability, and recommended phase 2 dose (RP2D) and schedule of trametinib in combination with gemcitabine. Secondary objectives included ...assessment of clinical activity and steady-state pharmacokinetics. Methods Adults with advanced solid tumours, adequate organ function and Eastern Co-operative Oncology Group performance status (ECOG PS) ⩽ 1 were eligible. Once-daily oral trametinib (1 mg, 2 mg, 2.5 mg) was escalated in a 3 + 3 design with standard gemcitabine dosing (1000 mg/m2 IV Days 1, 8, and 15 of 28-day cycles). During expansion, trametinib 2 mg was combined with gemcitabine. Pharmacokinetics samples were collected on Day 15 pre-dose and 1, 2, 4 and 6 h post-dose; tumour assessments were repeated every two cycles. Results Between 8/2009 and 11/2010, 31 patients (pancreas = 11, breast = 6, non-small cell lung cancer (NSCLC) = 4, other = 10) were treated. Dose-limiting toxicities (DLTs) occurred in each cohort, and included febrile neutropenia, transaminase elevation and uveitis. The RP2D was declared as trametinib 2 mg daily with standard gemcitabine dosing. Common grade 3/4 toxicities at the RP2D included: neutropenia (38%), thrombocytopenia (19%) and transaminase elevation (14%). Of 10 patients with measurable pancreatic cancer, three partial responses (30%) were documented; two additional patients achieved objective responses (breast, complete response (CR); salivary glands, partial response (PR)). Pharmacokinetics suggested no change in exposures of either drug in combination. Conclusion Administration of trametinib at its full monotherapy dose of 2 mg daily in combination with standard gemcitabine dosing (1000 mg/m2 IV Days 1, 8, and 15 every 28 days) was feasible. Though most toxicities were manageable, the addition of trametinib may increase gemcitabine-associated myelosuppression. Future studies of this combination will require monitoring to maintain dose and schedule.
This two-part study evaluated trametinib, a MEK1/2 inhibitor, in combination with anticancer agents. Inhibition of MEK, a downstream effector of KRAS, demonstrated preclinical synergy with ...chemotherapy in KRAS-mutant NSCLC cell lines. Part 1 of this study identified recommended phase 2 doses of trametinib combinations. Part 2, reported herein, evaluated the safety, tolerability, pharmacokinetics, and efficacy of trametinib combinations in patients with NSCLC with and without KRAS mutations.
Phase 1b evaluated trametinib plus docetaxel with growth factor support (trametinib, 2.0 mg once daily, and docetaxel, 75 mg/m2 every 3 weeks) or pemetrexed (trametinib, 1.5 mg once daily, and pemetrexed, 500 mg/m2 every 3 weeks). Eligibility criteria for the expansion cohorts included metastatic NSCLC with measurable disease, known KRAS mutation status, Eastern Cooperative Oncology Group performance status of 1 or lower, and no more than two prior regimens.
The primary end point of overall response rate (ORR) was met for both combinations. A confirmed partial response (PR) was observed in 10 of the 47 patients with NSCLC who received trametinib plus docetaxel (21%). The ORR was 18% (four PRs in 22 patients) in those with KRAS wild-type NSCLC versus 24% (six PRs in 25 patients) in those with KRAS-mutant NSCLC. Of the 42 patients with NSCLC treated with trametinib plus pemetrexed, six (14%) had a PR; the ORR was 17% (four of 23) in patients with KRAS-mutated NSCLC versus 11% (two of 19) in KRAS wild-type NSCLC. Adverse events—most commonly diarrhea, nausea, and fatigue—were manageable.
Trametinib-plus-chemotherapy combinations were tolerable. Clinical activity exceeding the ORRs previously reported with docetaxel or pemetrexed alone in KRAS-mutated NSCLC and meeting prespecified criteria was observed.
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