Clinical pharmacokinetics of bevacizumab in patients with solid tumors

Objective  To characterize the population pharmacokinetics of bevacizumab and the influence of demographic factors, disease severity, and concomitantly used chemotherapy agents on it’s pharmacokinetic behavior. Patients and methods  Data from eight clinical trials with bevacizumab administered by intravenous infusion were included. A total of 4,629 bevacizumab concentrations from 491 patients with solid tumors, who received bevacizumab doses ranging from 1 to 20 mg/kg at a dosing frequency ranging from weekly to every 3 weeks, were analyzed using a nonlinear mixed-effects modeling approach (NONMEM). Results  The best structural model was a two-compartment model with first-order elimination. In the final model, estimated clearance (CL) and central compartment volume of distribution (V _c) were 0.207 L/day and 2.39 L for a typical female. The terminal half-life estimate was ∼20 days for both men and women. Body weight and gender were the most significant covariates to explain interpatient variability for CL and V _c. Clearance was 26% faster in men than in women. Patients with low serum albumin and high serum alkaline phosphatase had 19 and 23% faster CL, respectively, than a typical patient. Consistent with the long elimination half life, simulations showed that similar steady-state exposures can be maintained when the weekly mg/kg dose rate is maintained, therefore allowing administration of bevacizumab to coincide with the frequency of administration of the cytotoxic agents. Conclusion  The PK parameters were consistent with those of other IgG molecules. The results support dosing bevacizumab on a once every 2 weeks or once every 3 weeks dosing schedule on a mg/kg basis.     

Phase I evaluation of the effects of ketoconazole and rifampicin on cediranib pharmacokinetics in patients with solid tumours

Purpose

To investigate any effect of a CYP3A4 inhibitor (ketoconazole) or inducer (rifampicin) on cediranib steady-state pharmacokinetics in patients with advanced solid tumours.

Methods

In two Phase I, open-label trials, patients received once-daily oral doses of cediranib alone [20 mg (ketoconazole study); 45 mg (rifampicin study)] for 7 days followed by cediranib at the same dose with ketoconazole 400 mg/day for 3 days or once-daily rifampicin 600 mg/day for 7 days, respectively. Patients then continued to receive once-daily cediranib.

Results

In the ketoconazole study, 46 patients were dosed; 38 were evaluable for C _ss,max, 36 for AUC_ss. gMean AUC_ss and C _ss,max for cediranib 20 mg increased by 21 % (94 % CI 9–35 %) and 26 % (94 % CI 10–43 %), respectively, in the presence of ketoconazole. In the rifampicin study, 64 patients were dosed; 44 were evaluable for C _ss,max and 41 for AUC_ss. gMean AUC_ss and C _ss,max for cediranib 45 mg decreased by 39 % (90 % CI 34–43 %) and 23 % (90 % CI 16–30 %), respectively, in the presence of rifampicin. gMean ratios for AUC_ss and C _ss,max were >1 for ketoconazole and <1 for rifampicin and CIs were outside the pre-specified equivalence boundaries, indicating a statistically significant effect. Significant inter-patient variability in cediranib AUC_ss and C _ss,max was observed. The safety profile of cediranib was similar to that reported previously.

Conclusions

Co-administration of ketoconazole or rifampicin had statistically significant effects on steady-state pharmacokinetics of cediranib in patients with advanced solid tumours. Therefore, caution is advised when administering cediranib with potent enzyme inhibitors or inducers.     

A Phase I study of pazopanib in combination with gemcitabine in patients with advanced solid tumors

Purpose

Pazopanib plus gemcitabine combination therapy was explored in patients with advanced solid tumors.

Methods

In a modified 3 + 3 enrollment scheme, oral once-daily pazopanib was administered with intravenous gemcitabine (Days 1 and 8, 21-day cycles). Three protocol-specified dose levels were tested: pazopanib 400 mg plus gemcitabine 1,000 mg/m², pazopanib 800 mg plus gemcitabine 1,000 mg/m², and pazopanib 800 mg plus gemcitabine 1,250 mg/m². Maximum-tolerated dose was based on dose-limiting toxicities during treatment Cycle 1. In the expansion phase, six additional patients were enrolled at the highest tolerable dose level.

Results

Twenty-two patients were enrolled. At the highest dose level tested (pazopanib 800 plus gemcitabine 1,250), patients received >80 % of their planned dose and the regimen was deemed safe and tolerable. The most common treatment-related adverse events included fatigue, neutropenia, nausea, and decreased appetite. Neutropenia and thrombocytopenia were the most common events leading to dose modifications. Pharmacokinetic interaction between pazopanib and gemcitabine was not observed. One objective partial response at the highest dose was observed in a patient with metastatic melanoma. Prolonged disease stabilization (>12 cycles) was reported in three patients (metastatic melanoma, cholangiocarcinoma, and colorectal carcinoma).

Conclusion

Combination pazopanib plus gemcitabine therapy is tolerable, with an adverse event profile reflective of that associated with the individual agents. There was no apparent pharmacokinetic interaction with pazopanib plus gemcitabine co-administration, although patient numbers were limited. Further investigation of combined pazopanib plus gemcitabine is warranted.     

Population pharmacokinetics of cabazitaxel in patients with advanced solid tumors

Purpose

To develop a population pharmacokinetic (PK) model for cabazitaxel in patients with advanced solid tumors and examine the influence of demographic and baseline parameters.

Methods

One hundred and seventy patients who received cabazitaxel (10–30 mg/m², 1-h IV infusion) every 7 or 21 days in five Phase I–III studies were analyzed by non-linear mixed-effect modeling (NONMEM VI). Model evaluation comprised non-parametric bootstrap and visual predictive checks.

Results

Cabazitaxel PK was best described by a linear three-compartment model with: first-order elimination; interindividual variability on clearance (CL), central volume of distribution (V1), and all intercompartmental rate constants except K21; interoccasion variability in CL and V1; proportional residual error of 27.8 %. Cabazitaxel CL was related to body surface area (BSA) and tumor type (breast cancer; finding confounded by study). Typical CL for a non-breast cancer patient with a BSA of 1.84 m² was 48.5 L/h, with V1 26.0 L, steady-state volume of distribution 4,870 L and alpha, beta, and gamma half-lives of 4.4 min, 1.6, and 95 h, respectively. Sex, height, weight, age, Caucasian race, renal/hepatic function, and cytochrome P450 inducer use did not significantly further explain the PK of cabazitaxel. Bootstrap and posterior predictive checks confirmed the adequacy of the model.

Conclusions

Cabazitaxel PK appears unaffected by most baseline patient factors, and the influence of BSA on CL is addressed in practice by BSA-dependent doses. This analysis suggests consistent cabazitaxel PK and exposure across most solid tumor types, although the potential influence of breast cancer on CL requires further confirmation.     

Phase I study of pazopanib in combination with weekly paclitaxel in patients with advanced solid tumors

Purpose.

To evaluate the maximum tolerated regimen (MTR), dose-limiting toxicities, and pharmacokinetics of pazopanib, an oral small-molecule tyrosine kinase inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit, in combination with paclitaxel.

Patients and Methods.

Pazopanib was given daily with weekly paclitaxel on days 1, 8, and 15 every 28 days. Dose levels of pazopanib (mg/day)/paclitaxel (mg/m²) were 400/15, 800/15, 800/50, and 800/80. An expanded cohort was enrolled at the MTR. Plasma samples were collected to evaluate the effect of pazopanib, an inhibitor of cytochrome P450 (CYP)3A4, on the pharmacokinetics of paclitaxel, a CYP3A4 and CYP2C8 substrate.

Results.

Of 26 enrolled patients, 17 were treated at the MTR of 800 mg pazopanib and 80 mg/m² paclitaxel. Dose-limiting toxicities included a grade 3 abscess and grade 2 hyperbilirubinemia. Other toxicities included elevated liver transaminases and diarrhea. Six patients (23%) had partial responses and 15 patients (58%) had stable disease. Administration of 800 mg pazopanib resulted in a 14% lower paclitaxel clearance and a 31% higher paclitaxel maximal concentration than with administration of paclitaxel alone at 15, 50, and 80 mg/m². At the MTR, coadministration of 800 mg pazopanib and 80 mg/m² paclitaxel resulted in a 26% higher geometric mean paclitaxel area under the curve.

Conclusion.

Pazopanib, at a dose of 800 mg daily, can be safely combined with a therapeutic dose of paclitaxel at 80 mg/m² when administered on days 1, 8, and 15, every 28 days. The observed greater plasma concentrations of paclitaxel given concurrently with pazopanib suggest that pazopanib is a weak inhibitor of CYP3A4 and CYP2C8.     

Phase 1 study of pazopanib alone or combined with lapatinib in Japanese patients with solid tumors

Purpose

A phase 1 study of pazopanib alone or in combination with lapatinib was conducted to assess the safety, tolerability, and pharmacokinetics of these oral tyrosine kinase inhibitors in Japanese patients with solid tumors.

Methods

In part A (monotherapy), 7 patients initially received pazopanib 800 mg/day, the recommended dose for non-Japanese patients. Then, 3 patients received pazopanib 400 mg/day on day 1 followed by 800 mg/day from day 2 onward. Three other patients received pazopanib 1,000 mg/day. In part B (combination therapy), 17 patients received pazopanib plus lapatinib (pazopanib/lapatinib) at once-daily doses of 400/1,000 mg (4 patients), 800/1,000 mg (3 patients), 400/1,500 mg (3 patients), and then 600/1,250 mg (7 patients).

Results

There was no dose-limiting toxicity during the study. In part A, most drug-related adverse events were grade 2 or lower, including neutropenia/neutrophil count decreased, thrombocytopenia/platelet count decreased, diarrhea, hypertension, aspartate aminotransferase increased, and lipase increased. In part B, rash, decreased appetite, and serum thyroid-stimulating hormone increased also occurred. In all dose groups, the plasma concentrations after multiple doses of pazopanib exceeded the target trough concentration for inhibition of vascular endothelial growth factor receptor-2 activity (20 μg/mL).

Conclusions

The pharmacokinetic profiles of pazopanib and lapatinib in Japanese patients were not apparently different from those reported in non-Japanese patients. There were no consistent trends in pharmacokinetic drug interactions between pazopanib and lapatinib. Pazopanib monotherapy at 800 and 1,000 mg once daily and pazopanib plus lapatinib once daily at any doses studied were well tolerated in Japanese patients.     

Safety and pharmacokinetics of panitumumab in Japanese patients with advanced solid tumors

Background  

Panitumumab is a fully human, monoclonal antibody against the epidermal growth factor receptor. Previous studies in non-Japanese patients with solid tumors showed that panitumumab exhibited nonlinear pharmacokinetics, was well tolerated (skin toxicities were the most common treatment-related adverse events), and had antitumor activity in some patients. This open-label, phase 1 study investigated panitumumab safety and pharmacokinetics in Japanese patients.     

Clinical pharmacokinetics of intravenous treosulfan in patients with advanced solid tumors

Treosulfan (l-threitol-1,4-bis-methanesulfonate, Ovastat) is a prodrug of a bifunctional alkylating agent with activity in ovarian carcinoma and other solid tumors. For a clinical and pharmacology study, patients with advanced, refractory, or resistant solid tumors were treated with a single-dose intravenous 30-min infusion of 8 or 10 g/m² treosulfan. A sensitive method for the determination of treosulfan in plasma and urine by reverse-phase high-performance liquid chromatography was developed. A total of 14 plasma and urine treosulfan pharmacokinetics determinations were analyzed in the 8-g/m² group and 7 were analyzed in the 10-g/m² group, the maximum tolerated dose for this group of pretreated patients. The terminal half-life of treosulfan was in the range of 1.8 h. AUC and C_max values were significantly (P < 0.01) higher in the 10-g/m² group (AUC 708 ± 168 versus 977 ± 182 μg ml⁻¹ h, C_max 465 ± 98 versus 597 ± 94 μg/ml). The mean urinary excretion of the parent compound was about 25% of the total dose delivered over 48 h (range 5–49%), and about 20% was excreted during the first 6 h after administration. Currently, a clinical phase I pharmacokinetics and dose-escalation trial with autologous blood stem-cell support has been started at 20 g/m² treosulfan using a 2-h infusion protocol. Received: 25 August 1997 / Accepted: 15 December 1997     

Oral vinorelbine pharmacokinetics and absolute bioavailability study in patients with solid tumors.

BACKGROUND: Vinorelbine is a vinca alkaloid obtained by hemisynthesis, which makes the molecule more lipophilic than the other vincas. An injectable formulation is already marketed for the treatment of non small cell lung cancer (NSCLC) and advanced breast cancer (ABC). A new oral form has been developed and its file registration is being submitted. As part of its development, a clinical study was conducted to determine the absolute bioavailability and pharmacokinetics of oral vinorelbine administered as softgel capsules, and to evaluate its safety profile compared with intravenous administration. PATIENTS AND METHODS: Thirty-two patients with solid tumours were included in the study. Patients fasted and were randomised to receive vinorelbine on day 1, either as a 20 minute intravenous (i.v.) infusion of 25 mg/m2 or as softgel capsules at a dose of 80 mg/m2. Patients were treated with the alternate route after a one week wash-out period. Blood and urine samples for pharmacokinetic analysis were collected during each vinorelbine administration. Safety was assessed after each administration using the CALGB/expanded CTC classification. RESULTS: Twenty-four patients were eligible for pharmacokinetic evaluation. Oral vinorelbine was rapidly absorbed at 80 mg/m2 (Tmax 1.4 +/- 0.7 h) and showed a bioavailability of 43 +/- 14, and close to 40% based on AUC(last) and AUC(inf), respectively. A bioequivalence analysis was conducted on dosage-normalised blood exposures. Equivalence was demonstrated between 80 mg/m2 oral and 30 mg/m2 i.v., and between 60 mg/m2 oral and 25 mg/m2 i.v. The inter-individual variability was equivalent for both routes (CV: 38% and 39% for oral and i.v., respectively). A correlation was found in both methods between AUClast and % nadir variation in white blood cells (WBC) and polymorphonuclears (PMN). More cases of neutropenia (all grades pooled), leucopenia (grades 3-4 only) and nausea (grades 2-3) were induced by 80 mg/m2 oral vinorelbine than by 25 mg/m2 i.v. The greatest intensity of these effects, following oral administration, probably reflects the higher, observed drug exposure. CONCLUSION: At therapeutic dosage levels, pharmacokinetic behaviour and safety profiles were similar for both routes. The absolute bioavailability of the oral vinorelbine (new, soft gelatine capsule) was close to 40%. Inter-individual variability in drug exposure was equivalent in both routes. The pharmacokinetic/pharmacodynamic (PK/PD) relationship in haematological toxicity was independent of the routes of administration. Reliable, corresponding doses between oral and i.v. vinorelbine were established, which will result in bioequivalent AUC.     

A Phase I and pharmacokinetics study of 2-chlorodeoxyadenosine in patients with solid tumors

 Preclinical studies of 2-chlorodeoxyadenosine (2-CdA) against solid tumors in the human tumor cloning assay and evidence that 2-CdA is active against slow-growing or resting tumor cells have stimulated interest in the clinical activity of this agent against solid tumors. This study sought to estimate the maximum tolerated dose, dose-limiting toxicity, and plasma and urine pharmacokinetics accompanying the intravenous administration of 2-CdA by 120-h continuous infusion in patients with solid tumors. Treated patients were also assessed for other toxicities of therapy and for antitumor response. A total of 23 patients received 35 courses of treatment given at doses of 3.5, 5.3, 6.5 and 8.1 mg/m² per day by continuous intravenous infusion for 5 days and repeated every 28 days. Blood and urine specimens were collected before, during, and after drug infusion. The dose-limiting toxicity at 8.1 mg/m² per day manifested as granulocytopenia in 2 of 5 patients (3 of 7 courses of treatment) and as thrombocytopenia in 3 of 5 patients (3 of 7 courses of treatment). At the dose levels of 6.5 and 8.1 mg/m² per day, recovery from thrombocytopenia was often delayed. Severe lymphocytopenia (<1,000/μl) was observed at all dose levels of 2-CdA. Dose-related anemia and leukopenia were observed and were infrequently severe. Nonhematological toxicities were confined to mild-to-moderate nausea, vomiting, fatigue, and anorexia. Fever of 37^°–40^°C was induced during drug infusion in 19 patients. No antitumor response was observed. Average plasma concentrations at steady-state (Cp_ss) ranged from 3 ng/ml at the initial dose level to 13 ng/ml at the dose level of 8.1 mg/m² per day. Both the Cp_ss and the area under the plasma concentration-time curve (AUC) were proportional to the dose. A relationship was observed between the percentage of change in absolute neutrophil count and the AUC. Renal excretion accounted for only 18% of the elimination of 2-CdA over the 5-day infusion period. The maximum tolerated dose for 2-CdA given by 5-day continuous infusion was 8.1 mg/m² per day in this study. The recommended dose on this schedule for phase II studies is 6.5 mg/m² per day. Granulocytopenia and thrombocytopenia were dose-limiting. No antitumor activity was observed during this study. On the basis of the plasma concentrations of 2-CdA observed, it is unlikely that this schedule of drug administration will permit achievement of the concentrations consistent with antitumor activity observed in preclinical studies. Received: 14 March 1994/Accepted: 22 July 1994     

A phase I pharmacokinetics study of 9-nitrocamptothecin in patients with advanced solid tumors

Purpose

9-Nitrocamptothecin (9-NC) is a novel orally administered camptothecin analog. The purpose of this study is to evaluate the pharmacokinetics and safety of 9-nitrocamptothecin in patients with advanced solid tumors.

Methods

The 23 patients for a single-dose pharmacokinetic experiment were divided into 3 dosing cohorts. The dosage of 9-nitrocamptothecin capsule was 1.25, 1.5 and 1.75 mg/m², respectively. The 8 patients for a multiple-dose pharmacokinetic study were orally administered 9-nitrocamptothecin 1.5 mg/m² for 5 consecutive days. Determination of the plasma concentration of 9-nitrocamptothecin was performed by high-performance liquid chromatography-ultraviolet detector technique, and determination of plasma concentration of 9-aminocamptothecin was performed by high-performance liquid chromatography-fluorescence detector technique.

Results

In the single-dose pharmacokinetic study, the mean ± SD 9-nitrocamptothecin C _max were 94.49 ± 41.38, 115.56 ± 63.27 and 147.57 ± 38.19 ng/mL; AUC_0–36 were 877.14 ± 360.90, 961.33 ± 403.58 and 1,189.75 ± 405.80 ng h/mL, respectively; the mean ± SD 9-aminocamptothecin C _max were 12.85 ± 6.46, 10.72 ± 6.58 and 28.74 ± 31.94 ng/mL; AUC_0–36 were 157.61 ± 111.61, 88.71 ± 39.51 and 173.52 ± 122.19 ng h/mL, respectively. In the multiple-dose pharmacokinetic study, the mean ± SD 9-nitrocamptothecin AUC_ss was 907.04 ± 736.47 ng h/mL, C _max was 85.98 ± 47.52 ng/mL, C _min was 18.91 ± 22.50 ng/mL, C _av was 37.79 ± 30.69 ng/mL, DF was 2.16 ± 0.87; the mean ± SD 9-aminocamptothecin AUC_ss was 442.73 ± 308.39 ng h/mL, C _max was 34.83 ± 18.31 ng/mL, C _min was 10.32 ± 6.95 ng/mL, C _av was 18.45 ± 12.85 ng/mL, DF was 1.34 ± 0.42. Comparing single-dose 1.5 mg/m² group with multiple-dose 1.5 mg/m² group, no significant difference was observed in 9-NC pharmacokinetic parameters, but with respect to the metabolite, significant differences were observed in C _max and AUC. The toxicity of 9-NC varied from mild to moderate. No grade 3 or grade 4 toxicity was observed during the study. There was 2- to 13-fold variabilities in 9-NC and 9-AC exposure among different patients for any given dose of 9-NC.

Conclusions

All participants had good tolerance throughout the study. 9-NC and 9-AC exposure did not increase proportionally to the dose ranging from 1.25 to 1.75 mg/m². After 5-day continuous administration, accumulation was observed in the metabolite 9-AC, but not in 9-NC.     

Effects of melatonin administration on cytokine production in patients with advanced solid tumors

There is growing evidence that the pineal gland has antineoplastic properties, which include the action of melatonin (MLT) on the immune system through the release of cytokines by activated T-cells and monocytes. Despite these intriguing preliminary findings, only few studies have been undertaken to date on MLT's action in cancer patients. The present study was carried out on 23 patients (15 males and 8 females, range 48-71 years), with advanced solid tumors, who received MLT (10 mg/day orally for a month) after conventional therapy. Blood was assayed for tumor necrosis factor alpha (TNF-alpha), Interleukin-2 (IL-2) and human interferon gamma (IFN-gamma). Blood samples were taken immediately before the start of MLT administration and 30 days after therapy. Plasma was collected in EDTA tubes on ice, centrifuged immediately at 4-degrees-C and stored frozen at -80-degrees-C until assayed. Cytokines were quantified by immunoradiometric assays. Circulating levels of TNF-alpha, IL-2 and IFN-gamma increased by 28%, 51% and 41% respectively after MLT administration. These increments were statistically significant (paired Student's t-test, p<0.01). These findings are consistent with the hypothesis that MLT modulates immune functions in cancer patients by activating the cytokine system.     

A randomized, double-blind, placebo-controlled study to evaluate the effect of repeated oral doses of pazopanib on cardiac conduction in patients with solid tumors

Purpose

As tyrosine kinase inhibitors have been associated with cardiotoxicity, we evaluated the effect of pazopanib, an inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit, on electrocardiographic parameters in patients with cancer.

Methods

This double-blind, placebo-controlled, parallel-group study randomized patients (N = 96) to moxifloxacin (positive control) or placebo on Day 1 followed by pazopanib or placebo 800 mg/day (fasted) on Days 2–8 and 1,600 mg (with food) on Day 9. Treatment effects were evaluated by baseline-adjusted, time-matched, serial Holter electrocardiograms.

Results

Sixty-five patients were evaluable for preplanned analyses. On Day 1, the maximum mean difference in baseline-adjusted, time-matched Fridericia-corrected QT (QTcF) interval in moxifloxacin-treated patients versus placebo was 10.6 ms (90 % confidence interval [CI]: 4.2, 17.0). The administration scheme increased plasma pazopanib concentrations approximately 1.3- to 1.4-fold versus the recommended 800 mg once-daily dose. Pazopanib caused clinically significant increases from baseline in blood pressure, an anticipated class effect, and an unexpected reduction in heart rate from baseline that correlated with pazopanib exposure. On Day 9, the maximum mean difference in baseline-adjusted, time-matched QTcF interval in pazopanib-treated patients versus placebo was 4.4 ms (90 % CI: ?2.4, 11.2). Mixed-effects modeling indicated no significant concentration-dependent effect of pazopanib or its metabolites on QTcF interval.

Conclusions

Pazopanib as administered in this study achieved supratherapeutic concentrations, produced a concentration-dependent decrease in heart rate, and caused a small, concentration-independent prolongation of the QTcF interval.     

Phase I study of the effects of renal impairment on the pharmacokinetics and safety of satraplatin in patients with refractory solid tumors

BackgroundSatraplatin is an oral platinum analog with demonstrated activity in a range of malignancies. The current study was designed to evaluate the effect of varying degrees of renal impairment on the safety and pharmacokinetics (PKs) of satraplatin.Patients and methodsPatients with advanced solid tumors, refractory to standard therapies, were eligible. The study included four cohorts of patients with varying levels of renal function, and eight patients per cohort: Group 1 (G1) = normal renal function; G2 = mild renal impairment [creatinine clearance (CrCl) 50–80 ml/min]; G3 = moderate impairment (CrCl 30 to <50 ml/min); G4 = severe impairment (CrCl <30 ml/min). Satraplatin was administered orally at 80 mg/m²/day on days 1–5 every 35 days.ResultsA total of 32 patients were enrolled, 8 patients in each renal function group. Each group tolerated the dose of 80 mg/m²/day on days 1–5 every 35 days without the need for dose deescalation. The most common adverse events were fatigue (63%), nausea (56%), diarrhea (53%), anorexia (47%), constipation (38%), vomiting (28%), anemia, dyspnea, and thrombocytopenia (25%). There were no dose-limiting toxic effects in any study group. There was increased exposure to plasma platinum and plasma ultrafiltrate platinum in patients with moderate to severe renal impairment.ConclusionsSatraplatin PKs was altered in patients with renal impairment. However, a corresponding increase in satraplatin-related toxic effects was not observed.     

Effect of food on the pharmacokinetics of TAS‐102 and its efficacy and safety in patients with advanced solid tumors

TAS‐102, a novel oral antitumor agent, consists of trifluridine and tipiracil hydrochloride (molar ratio, 1:0.5). We investigated the effects of food on trifluridine and tipiracil hydrochloride. The efficacy and safety of TAS‐102 were evaluated in patients with advanced solid tumors. We analyzed drug pharmacokinetics using a randomized, single‐dose, two‐treatment (fed versus fasting), two‐period, two‐sequence cross‐over design, followed by repeated administration. Patients were given single doses of TAS‐102 (35 mg/m²) in the pharmacokinetic phase and received twice‐daily doses of TAS‐102 in 28‐day cycles in the repeated administration phase for evaluating efficacy and safety. Food showed no effect on the area under the curve from 0 to 12 h or 0 h–infinity values of trifluridine following administration of TAS‐102 under fasting and fed conditions, whereas those of tipiracil hydrochloride decreased by approximately 40%. Maximum concentrations of both drugs decreased by approximately 40%, indicating that food influenced the absorption and bioavailability of trifluridine and tipiracil hydrochloride, respectively. During the repeated administration, stable disease was observed in nine patients with rectal, small‐cell lung, breast, thymic, duodenal, and prostate cancers. Major adverse events were neutropenia, leukopenia, anemia, and nausea. Postprandial administration was optimal for TAS‐102 because trifluridine's area under the curve was not changed by food, indicating that its clinical efficacy would not be affected. Additionally, postprandial administration was reasonable because the maximum concentration of trifluridine decreased in neutrophils, which correlated with previous studies. These results suggest that TAS‐102 would be an effective treatment for small‐cell lung, thymic, and colorectal cancers. This trial is registered with the Japan Pharmaceutical Information Center (no. JapicCTI‐111482).     

Safety and pharmacokinetics of high-dose gefitinib in patients with solid tumors: results of a phase I study

Purpose  

Previous studies established the safety of continuous gefitinib 250 or 500 mg daily. It was postulated that a higher dose may have increased efficacy by inhibiting signaling in both the mitogen-activated protein kinase and AKT pathways. This study investigated the tolerability, pharmacokinetics, and antitumor activity of high-dose gefitinib in patients with refractory solid malignancies.     

Phase I study to assess the pharmacokinetics and the effect on cardiac repolarization of amrubicin and amrubicinol in patients with advanced solid tumors

Purpose

To evaluate the pharmacokinetics and cardiac repolarization effect (measured by QT/QTc interval) of amrubicin and its active metabolite amrubicinol in non-Japanese patients with advanced solid tumors.

Methods

Patients received amrubicin 40 mg/m²/day as a 5-min infusion on days 1–3 of a 21-day cycle. During cycle 1, serial blood and plasma samples were collected on days 1–9 and time-matched triplicate electrocardiograms on the “off-drug” visit (1–5 days prior to start of treatment) and days 1–9.

Results

Twenty-four patients were treated. Amrubicinol reached peak concentration 2–4 h after amrubicin administration and had a terminal half-life of 53 h. Distribution of amrubicinol into erythrocytes was fivefold greater than into plasma. The molar ratio of amrubicinol to amrubicin in blood was 0.67 on day 3. The presence of an NQO1 polymorphism did not alter drug exposure. The upper bound of the one-sided 95 % confidence interval for the time-matched, baseline-adjusted change from the off-drug day in QTcI (individual correction) was <10 ms at all times and was only >10 ms (10.20 ms) at a single time point for QTcF (Fridericia correction). No relationship was observed between blood amrubicin or amrubicinol concentrations and QTcF changes. All QTcF measurements were <480 ms, and none increased by >60 ms from baseline.

Conclusions

Data suggest that amrubicinol is an important active metabolite in humans and that both compounds were not associated with clinically relevant QTc interval prolongation at the dose regimen studied.