Key pharmacokinetic parameters of isepamicin in febrile neutropenic cancer patients and in women with acute pelvic inflammatory disease

The pharmacokinetics (PK) of isepamicin were studied in 8 febrile neutropenic patients with hematologic malignancy and in 20 young women with acute pelvic inflammatory disease (PID). Isepamicin was given as a slow intravenous infusion over 30 min at a dose of 15 mg/kg once daily (OD). Serum levels of isepamicin were determined by fluorescence polarization immunoassay, and PK analyses were obtained based on a one-compartment open model after 24 hours (steady state) and after 7 days. On day 1, the volume of distribution (Vd) of isepamicin, for both populations, appeared about 30% higher than classically reported in healthy individuals: 0.31 and 0.36 L/kg for neutropenic and PID patients respectively. However on day 7, Vd displayed significant reduction (0.28 and 0.27 L/kg, respectively for neutropenic and PID patients). A reduction of isepamicin clearance was also observed between day 1 and day 7 (137 vs 120 mL/min and 130 vs 101 mL/min for neutropenic and PID populations, respectively). Such changes are consistent with a significant increase in the Cmax concentrations (45 vs 50 mg/L, and 38 vs 49 mg/L) and in the AUC (136 vs 158 and 137 vs 162 mg/L.h) observed after a week of treatment in neutropenic and PID patients, respectively. In conclusion, taking into account the importance of reaching early active concentrations, we recommend the use of higher loading dose of isepamicin (>15 mg/kg) in neutropenic cancer patients and in women with PID, particularly in case of a combination with a possibly ineffective antibacterial agent, in case of infection with bacteria at upper limit of susceptibility, in the presence of high infectious inoculum or in the presence of sequestered sites of infection.     

Phase I dose-finding study and a pharmacokinetic/pharmacodynamic analysis of the neutropenic response of intravenous diflomotecan in patients with advanced malignant tumours

Purpose: To determine the maximum tolerated dose (MTD) of intravenous (iv) diflomotecan administered once every 3 weeks, and to characterize the relationship between pharmacokinetics and neutropenic effect, using a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model. Experimental design: Twenty-four patients received a total of 75 cycles of iv diflomotecan that was administered as 20-min infusion, once every 3 weeks at escalating doses of 2, 4, 5, and 6 mg/m². Haematological and non-haematological toxicities were evaluated. Plasma concentrations of diflomotecan were measured after the first drug administration. Results: Dose limiting toxicity (DLT) following the first cycle occurred in 12 patients and a total of 16 patients experienced DLT at some point in the trial. During the first cycle of treatment the number of patients in the 5 and 6 mg/m² dose groups that experienced DLT was 3 of 4, and 3 of 3, respectively. Therefore, the dose of 5 mg/m² was considered the MTD and the dose of 4 mg/m² the recommended dose (RD). During the first cycle, 12 patients experienced DLT, six had either infection of haematological toxicity and eight complained of fatigue. The best response was a partial response in one patient treated at the 6 mg/m² dose level. Disease stabilization was observed in seven patients (four patients treated at 4 mg/m² and one patient at each dose level of 2, 5, and 6 mg/m²). The remaining patients had all progressive disease. The median time to progression for all patients was 5.9 weeks. Pharmacokinetics of diflomotecan was described with a three-compartmental model. Mean population parameter estimates of the apparent volume of distribution of the central compartment (V _c) increased linearly with body surface area (BSA) as: V _c (L) = 41.5 × (BSA/1.85), and the mean population estimate of the apparent volume of distribution of the shallow compartment was lower in females (29.5 vs 48.8 L). Computer simulations showed the lack of clinical significance of these covariates. The time course of the neutropenic response was adequately described by a semi-mechanistic model that includes cellular processes and drug effects. Conclusions: The MTD and RD after a 20-min iv infusion of diflomotecan every 3 weeks are 4 and 5 mg/m², respectively. Diflomotecan showed linear pharmacokinetic behaviour and the selected PK/PD model described adequately the time course of neutropenia. The mean model predicted values of nadir and time to nadir after a 20-min iv infusion of 4 mg/m² of diflomotecan was 0.86 × 10⁹ /L neutrophil cell counts and 11 days, respectively. Part of this work was presented as a poster in the 12th Population Approach Group in Europe (PAGE) meeting [12–13, June, 2003, Verona (Italy)]and in the Annual meeting of American Society of Clinical Oncology (ASCO) in 2004.     

Population pharmacokinetic analysis of free and bound aflibercept in patients with advanced solid tumors

Objective

Aflibercept (Zaltrap^®) is a novel antiangiogenic agent that binds to vascular endothelial growth factor (VEGF) and inhibits VEGF-dependent tumor growth. We aimed to characterize the population pharmacokinetics (PK) of free and bound aflibercept in patients with solid tumors to examine the influence of covariates on their PK and to evaluate the proposed dosing regimens by simulation.

Methods

Data from 9 clinical trials with 1,506 cancer patients receiving aflibercept (2–9 mg/kg every 2 or 3 weeks; 1 h IV infusion) as a monotherapy or in combination with various chemotherapies were included. Free and bound aflibercept concentrations were analyzed using a non-linear mixed-effects modeling approach with MONOLIX 4.1.2.

Results

An approximation of a target-mediated drug disposition model with irreversible binding of free aflibercept to VEGF adequately described the PK of free and bound aflibercept. The typical estimated clearances for free (CL _f ) and bound aflibercept (CL _b ) were 0.88 and 0.19 L/day, respectively. The volumes of distribution for free (V _p ) and bound (V _b ) aflibercept were similar (~4 L). CL _f and V _p increased with body weight and were lower in women. Patients with low albumin (ALB) or high alkaline phosphatase (ALK) had faster CL _f compared to a typical patient. Pancreatic cancer may be associated with changes in binding of aflibercept to VEGF. Simulations of different dosing regimens showed that adequate saturation of circulating VEGF was achieved with a dose of 4 mg/kg every 2 weeks.

Conclusions

Aflibercept kinetics was most affected by gender, body weight, ALB, ALK and pancreatic cancer. Simulations supported the rationale for the recommended dose of 4 mg/kg every 2 weeks for aflibercept.     

Characterization of the long-term pharmacokinetics of bevacizumab following last dose in patients with resected stage II and III carcinoma of the colon

Purpose

The study characterizes the long-term pharmacokinetics (PK) following last dose of bevacizumab as adjuvant therapy in patients with resected stage II and III colon carcinoma in a Phase III clinical study (AVF3077s).

Methods

Patients in AVF3077s received bevacizumab (5 mg/kg every 2 weeks) as adjuvant therapy for 1 year. Following the last dose bevacizumab concentration, data at 3 and 6 months were used to characterize long-term bevacizumab PK based on the population-modeling approach.

Results

The long-term bevacizumab PK were consistent with previously reported results based on short-term bevacizumab PK. The clearance (CL), central volume of distribution (V ₁), intercompartmental clearance (Q), and the peripheral volume of distribution (V ₂) were 214 mL/day, 2,830 mL, 636 mL/day, and 2,490 mL, which correspond to a disposition and elimination half-life of 1.33 and 19.1 days, respectively. The empirical Bayes estimates of median post-treatment bevacizumab drug levels at 3 and 6 months were 6.14 and 0.23 μg/mL, respectively. For test covariates, the change in CL and V ₁ of bevacizumab was less than 20 % of the typical value. Body weight is the important covariate explaining the inter-individual variability on CL and V ₁.

Conclusions

Long-term bevacizumab PK in this study was predictable based on short-term PK data from metastatic settings in other tumor types. An exploratory analysis demonstrated no apparent association of the tested covariates with bevacizumab PK. Further, the extended serum persistence of bevacizumab following last dose should be considered in clinical study designs and post-treatment evaluations that may be affected by bevacizumab.     

Diffusion of Isepamicin into Cancellous and Cortical Bone Tissue

Abstract

The degree of penetration of an antibiotic into the infection site is an important factor in its therapeutic efficacy, particularly in bone and joint infections. In the present study, we examined the bone tissue penetration of isepamicin at a dose of 15 mg/Kg, and the results were correlated to microbiologic data to estimate the clinical efficacy of isepamicin in bone infections.

In this open-label, single-arm, noncomparative study, subjects of similar age, body weight, height and creatinine clearance who were undergoing elective total hip replacement received a single, parenteral 15 mg/Kg dose of isepamicin. Plasma and bone tissue samples were collected a mean 1.3 hours later and analyzed by a high-pressure liquid chromatography method.

Twelve patients (3 men and 9 women; mean age, 73.5 years; mean body weight, 53.5 Kg, mean creatinine clearance, 58.5 mL/min) were enrolled. The mean ± SD plasma concentration of isepamicin at the time of bone removal was 43.0 ± 10.4 μg/mL. The mean ± SD isepamicin concentrations were 11.6 ± 7.1 μg/mL in cancellous bone tissue and 12.0 ± 7.3 μg/mL in cortical bone tissue. The mean ± SD ratios of isepamicin concentration in bone and plasma (bone/plasma) were 0.28 ± 0.14 for cancellous bone tissue and 0.31 ± 0.20 for cortical bone tissue.

The concentrations achieved in both cancellous and cortical bone tissue were greater than the minimum concentrations required to inhibit the growth of 90% of strains (MIC₉₀) of most of the susceptible pathogens commonly involved in bone infections.     

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.     

Population pharmacokinetics of trastuzumab emtansine (T-DM1), a HER2-targeted antibody–drug conjugate,in patients with HER2-positive metastatic breast cancer: clinical implications of the effect of covariates

Purpose

Trastuzumab emtansine (T-DM1) is an antibody–drug conjugate comprising the humanized monoclonal antibody trastuzumab linked to DM1, a highly potent cytotoxic agent. A population pharmacokinetic (PK) analysis was performed to estimate typical values and interindividual variability of T-DM1 PK parameters and the effects of clinically relevant covariates.

Methods

Serum samples were collected from 671 patients with human epidermal growth factor receptor 2-positive locally advanced or metastatic breast cancer (MBC) who received single-agent T-DM1 in five phase I to phase III studies. Nonlinear mixed-effects modeling with the first-order conditional estimation method was used.

Results

A linear two-compartment model with first-order elimination from the central compartment described T-DM1 PKs in the clinical dose range. T-DM1 elimination clearance was 0.676 L/day, volume of distribution in the central compartment (V _c) was 3.127 L, and terminal elimination half-life was 3.94 days. Age, race, region, and renal function did not influence T-DM1 PK. Given the low-to-moderate effect of all statistically significant covariates on T-DM1 exposure, none of these covariates is expected to result in a clinically meaningful change in T-DM1 exposure.

Conclusions

T-DM1 PK properties are consistent and predictable in patients. A further refinement of dose based on baseline covariates other than body weight for the current 3.6 mg/kg regimen would not yield clinically meaningful reductions in interindividual PK variability in patients with MBC.     

Phase I and pharmacokinetic study of lexatumumab (HGS-ETR2) given every 2 weeks in patients with advanced solid tumors

BackgroundLexatumumab (HGS-ETR2) is a fully human agonistic mAb to the tumor necrosis factor-related apoptosis-inducing ligand receptor 2 that activates the extrinsic apoptosis pathway and has potent preclinical antitumor activity.Materials and methodsThis phase 1, dose escalation study assessed the safety, tolerability, pharmacokinetics (PKs) and immunogenicity of lexatumumab administered i.v. every 14 days in patients with advanced solid tumors.ResultsThirty-one patients received lexatumumab over five dose levels (0.1–10 mg/kg). Most (26 of 31) received four or more cycles of treatment. One patient at 10 mg/kg experienced a possibly related dose-limiting toxicity of grade 3 hyperamylasemia. Nine patients achieved stable disease. One patient with chemotherapy-refractive Hodgkin's disease experienced a mixed response. Lexatumumab PKs were linear up to 10 mg/kg. At the 10 mg/kg dose, the mean (±standard deviation) t_1/2b was 13.67 ± 4.07 days, clearance was 4.95 ± 1.93 ml/day/kg, V₁ was 45.55 ml/kg and V_ss was 79.08 ml/kg, indicating that lexatumumab distributes outside the plasma compartment. No human antihuman antibodies were detected.ConclusionsLexatumumab can be safely administered every 14 days at 10 mg/kg. The PK profile supports this schedule. Further evaluation of lexatumumab at this dose schedule is warranted, including combination trials with other agents.     

Phase I dose-finding and pharmacokinetic study of paclitaxel and carboplatin with oral valspodar in patients with advanced solid tumors.

PURPOSE: To evaluate the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetic (PK) profile of paclitaxel and carboplatin when administered every 3 weeks with the oral semisynthetic cyclosporine analog valspodar (PSC 833), an inhibitor of P-glycoprotein function. PATIENTS AND METHODS: Fifty-eight patients were treated with escalating doses of paclitaxel ranging from 54 to 94.5 mg/m(2) and carboplatin area under the plasma concentration versus time curve (AUC) ranging from 6 to 9 mg.min/mL, every 21 days. The dose of valspodar was fixed at 5 mg/kg every 6 hours for a total of 12 doses from day 0 to day 3. The MTD was determined for the following two groups: (1) previously treated patients, where paclitaxel and carboplatin doses were escalated; and (2) chemotherapy-na?ve patients, where paclitaxel dose was escalated and carboplatin AUC was fixed at 6 mg.min/mL. PK studies of paclitaxel and carboplatin were performed on day 1 of course 1. RESULTS: Fifty-eight patients were treated with 186 courses of paclitaxel, carboplatin, and valspodar. Neutropenia, thrombocytopenia, and hepatic transaminase elevations were DLTs. In previously treated patients, no DLTs occurred at the first dose level (paclitaxel 54 mg/m(2) and carboplatin AUC 6 mg.min/mL). However, one of 12, two of six, two of four, four of 11, and two of five patients experienced DLTs at doses of paclitaxel (mg/m(2))/carboplatin AUC (mg.min/mL) of 67.5/6, 81/6, 94.5/6, 67. 5/7.5, and 67.5/9, respectively. In chemotherapy-na?ve patients, one of 17 developed DLT at paclitaxel 81 mg/m(2) and carboplatin AUC 6 mg/mL.min. There was prolongation of the terminal phase of paclitaxel elimination as evidenced by an increased time that plasma paclitaxel concentration was >/= 0.05 micromol/L, ranging from 16.6 +/- 6.7 hours to 41.5 +/- 9.8 hours for paclitaxel doses of 54.5 mg/m(2) to 94.5 mg/m(2), respectively. CONCLUSION: The recommended phase II dose in chemotherapy-na?ve patients is paclitaxel 81 mg/m(2), carboplatin AUC 6 mg.min/mL, and valspodar 5 mg/kg every 6 hours. In previously treated patients, the recommended phase II dose is paclitaxel 67.5 mg/m(2), carboplatin AUC 6 mg.min/mL, and valspodar 5 mg/kg every 6 hours. The acceptable toxicity profile supports the rationale for performing disease-directed evaluations of paclitaxel, carboplatin and valspodar on the schedule evaluated in this study.     

Temporary Interruption of Ceftazidime Continuous Infusion Without Reduction of Activity: A Computer-Assisted Simulation

Abstract

Continuous infusion (CI) of ceftazidime has been demonstrated to add clinical advantages in the treatment of infection of neutropenic cancer patients, especially in the presence of Gram-negative bacteremia. However, this particular administration route is not always feasible in this particular clinical setting because of the patient's need of additional care or drug administration. The aim of this study was to evaluate, through a computer-assisted simulation, the modifications of drug concentration in presence of a single or repeated 2-hour interruptions of CI ceftazidime in critically ill patients.

Our analysis shows that a loading dose of 20 mg/kg, followed by a CI of 100/mg/kg/die, should be able to maintain efficacious plasma concentrations in all subjects, even when it is interrupted for a 2-hour period every 8 hours. Plasma concentrations after interruption should not fall below 8 μg/mL and for about 65-80% of time should reach levels equal to 5 times the MIC of the infecting pathogen.

A 2-hour interruption of CI ceftazidime up to 3 times a day is likely to represent a safe and efficacious administration regimen that may enhance the management of the treatment of infectious complications in critically ill patients such as neutropenic cancer patients.     

A phase 1 study of weekly everolimus (RAD001) in combination with docetaxel in patients with metastatic breast cancer

BACKGROUND:

Inhibition of mammalian target of rapamycin with everolimus may improve the efficacy of taxanes. Everolimus and docetaxel are both metabolized by CYP3A4, which could result in a pharmacokinetic (PK) interaction.

METHODS:

Fifteen patients with metastatic breast cancer were treated with docetaxel (doses of 40‐75 mg/m² intravenously on day 1 of a 21‐day cycle) in combination with everolimus (doses ranging from 20 to 50 mg orally on days 1 and 8 of a 21‐day cycle) in a phase 1 trial using the continuous reassessment method to determine maximum tolerated dose. The first 2 patients developed a dose‐limiting toxicity (neutropenic infection), prompting a mandatory dose reduction and PK evaluation of both everolimus and docetaxel for patients enrolled in subsequent dosing cohorts.

RESULTS:

Fifteen patients were treated. Dose‐limiting toxicity included grade 3 mucositis (n = 1), prolonged grade 4 neutropenia (n = 1), and grade 3 infection/febrile neutropenia (n = 3). Day 8 of everolimus was commonly held for neutropenia despite a dose reduction in docetaxel to 40 mg/m². Eleven patients underwent complete PK evaluation for everolimus, and 9 patients underwent complete PK evaluation for both everolimus and docetaxel. Widely variable changes in clearance were seen for both drugs, and the study was terminated because of lack of efficacy and concerns regarding toxicity seen with the combination.

CONCLUSIONS:

Weekly everolimus in combination with docetaxel every 3 weeks was associated with excessive neutropenia and variable clearance of both drugs, making combination therapy unpredictable, even at low doses of both drugs. Cancer 2012. © 2011 American Cancer Society.     

Population pharmacokinetics of dimethylacetamide in children during standard and once-daily IV busulfan administration

Purpose

N,N-dimethylacetamide (DMA) is administered to children during high-dose chemotherapy as a solubilizer with the intravenous formulation of busulfan (Busilvex^®). DMA has shown liver toxicity in rats. However, little is known regarding its pharmacokinetics (PK) in humans. The aim of this analysis was to compare the PK of DMA after a once-daily dose of Busilvex^® with the standard scheme consisting of 3–4 administrations per day in children.

Methods

Out of 42 children, aged 0.1–18.9 years, receiving Busilvex^®, 18 children received the first dose as a loading dose, giving a double dose of 1.4–2.0 mg/kg over a 4 h infusion followed by 15 doses of 0.7–1.0 mg/kg as 2 h infusions every 6 h. The other 24 children received Busilvex^® as 3 h infusions once-daily for 4 consecutive days with a targeted busulfan AUC of 4,263 μM*min. Using NONMEM? plasma, concentration–time data were analyzed. Assuming an increase in clearance overtime as found in our previous investigation, separate time factors for the two different dosing schedules included in the dataset were tested.

Results

A one-compartment model with clearance increasing over time described the DMA kinetics sufficiently. Peak plasma concentrations of DMA, up to 3.09 mmoL/L (median 0.75 mmoL/L) for the current licensed dose regimen and up to 8.77 mmoL/L (median 3 mmoL/L) for the once-daily application, were observed. The examined increase in clearance was found to be 58 mL/h/kg and 6.1 mL/h/kg per day for the current licensed and the once-daily dose regimen, respectively.

Conclusion

N,N-dimethylacetamide as solvent of lipophilic drugs such as busulfan has a linear PK in children of all ages using a dose split into one or four administrations per day. The rapid clearance with different dosing in patients of different body weights indicates that it is safe to use DMA in children in both a once and four times daily regimen.     

A Phase I Dose Escalation Study of the Safety,Tolerability, and Pharmacokinetics of Ipilimumab in Chinese Patients with Select Advanced Solid Tumors

Lessons Learned

• The overall safety profiles of ipilimumab 3 mg/kg and 10 mg/kg administered every 3 weeks, were consistent between Chinese patients with solid tumors in the current study and patients from previous U.S. ipilimumab monotherapy studies. No new safety signals were identified.
• The mean systemic exposures to ipilimumab (assessed by first dose area under the curve during the dosing interval and maximum serum concentration) were numerically lower in the Chinese patient population than in U.S. patients for both 3 mg/kg and 10 mg/kg doses; however, the range of serum concentrations in the Chinese and U.S. populations overlapped (3 mg/kg and 10 mg/kg), suggesting that ipilimumab pharmacokinetics was ethnically insensitive in this study.

BackgroundThis phase I, open‐label study assessed ipilimumab safety, tolerability, pharmacokinetics (PK), immunogenicity, and antitumor activity in Chinese patients with unresectable, metastatic, recurrent malignant melanoma (MM) or nasopharyngeal carcinoma (NPC).MethodsOf 39 patients enrolled, 25 received ipilimumab (11 patients received 3 mg/kg, and 14 patients received 10 mg/kg). Reasons for not receiving treatment were withdrawal of consent (3 patients), no longer meeting the criteria (10 patients), and one recorded as “other.” During the induction phase, patients received ipilimumab (3 mg/kg, i.v.), on day 1 of a 3‐week cycle, to a maximum of four doses or progressive disease (PD). During the maintenance phase at week 24, patients received ipilimumab (3 mg/kg, i.v.) on day 1 of a 12‐week cycle, to a maximum of 3 years or PD. Considering the co‐primary safety and PK endpoints, the successive dosing required nine patients with two or fewer dose‐limiting toxicities during the 42‐day observation period to proceed with a new cohort of nine patients at 10 mg/kg.ResultsIpilimumab safety and PK profiles were similar in Chinese and predominantly White populations. Ipilimumab was well tolerated. Most adverse events (AEs) were grades 1–2 and experienced by 11 patients treated with 3 mg/kg and 14 patients treated with 10 mg/kg. There were no new safety concerns. Incidence of anti‐ipilimumab antibodies was low (1 of 10 in the 3 mg/kg patients and 2 of 13 in the 10 mg/kg patients) and without safety implications. In the 3 mg/kg group, 8 of 11 patients had PD. In the 10 mg/kg group (all NPC, 0 MM patients), 11 of 14 patients had PD. Three patients had stable disease (one at 3 mg/kg and two at 10 mg/kg).ConclusionIpilimumab was well tolerated in Chinese patients, showing similar safety and PK to previous studies in predominantly White populations.     

Efficacy and safety of micafungin for treatment of serious Candida infections in patients with or without malignant disease

The aim of this study was to evaluate micafungin efficacy for treatment of invasive candidiasis/candidaemia in patients with cancer. Modified intent-to-treat populations were analysed from two trials: one, in adults and children with confirmed Candida infection, compared micafungin (adults 100 mg day(-1); children 2 mg kg(-1) day(-1)) with liposomal amphotericin B (L-AmB 3 mg kg(-1) day(-1)); and the other, in adults only, compared micafungin (100 or 150 mg day(-1)) with caspofungin (50 mg day(-1); 70 mg loading dose). Primary efficacy endpoint in both trials was treatment success, defined as both clinical and mycological response at end of therapy. In the micafungin/L-AmB trial, 183/489 patients had malignancy (37% neutropenic). In the micafungin/caspofungin trial, 176/572 patients had malignancy (26% neutropenic). Micafungin treatment success rates were generally similar in patients with/without malignancy and to rates observed with L-AmB and caspofungin. Most patients with malignancy and neutropenia were successfully treated by all three drugs. For all drugs, incidence of discontinuations because of treatment-related adverse events was similar for patients with malignancy (≤7.7%) vs. no malignancy (≤8.0%). These results suggest that compared with L-AmB and caspofungin, micafungin was effective and well tolerated in patients with candidiasis/candidaemia with/without malignancy. Further prospective trials are recommended to evaluate comparative outcomes with a primary focus on patients with malignancies and invasive candidiasis.     

A phase I pharmacokinetic study of bexarotene with vinorelbine and cisplatin in patients with advanced non-small-cell lung cancer (NSCLC)

Purpose

This is a phase I study of the retinoid X receptor agonist bexarotene (Targretin^®) in combination with the chemotherapeutic drugs cisplatin and vinorelbine and lipid-lowering therapy. This study looked for pharmacokinetic (PK) interactions between the agents in parallel with a phase III study of the combination.

Methods

Patients (n = 26) with advanced-stage non-small-cell lung cancer received intravenous cisplatin 100 mg/m² on day 1 and at 4-week intervals plus intravenous vinorelbine 25 mg/m² weekly. Continuous oral bexarotene therapy (400 mg/m²/day) was initiated at day 4. Lipid-lowering therapy was initiated in all patients due to hypertriglyceridemia associated with bexarotene use. PK profiles of the chemotherapeutic agents were obtained on day 1 (without bexarotene) and during cycles 2–4 (with bexarotene). Vinorelbine (n = 18) and free cisplatin (n = 17) PK parameters in evaluable patients were determined using non-compartmental methods.

Results

Mean vinorelbine and free cisplatin clearance and dose-corrected AUC values with bexarotene were within 20% of respective values without concomitant bexarotene. Bexarotene levels did not vary with or without co-administration of the chemotherapeutic agents. There was no evidence of increased toxicity when bexarotene was co-administered with the chemotherapeutic agents.

Conclusions

Bexarotene does not substantially affect vinorelbine or cisplatin PK, and the combination is well tolerated. The results are consistent with the mechanisms of elimination of vinorelbine (high metabolic clearance) and cisplatin (non-enzymatic and renal elimination).

     

The pharmacokinetics and toxicity of the anthrapyrazole anti-cancer drug CI-941 in the mouse: a guide for rational dose escalation in patients

Summary CI-941 is a new synthetic DNA-binding agent selected for phase I clinical evaluation. The drug has broad-spectrum antitumour activity against a number of murine tumours and, in contrast to doxorubicin, is unlikely to induce cardiotoxicity by a free-radical-mediated mechanism. In this study the toxicity and pharmacokinetics of CI-941 were studied in the mouse to enable the implementation of a pharmacokinetically guided dose-escalation strategy in patients. Following a single i.v. bolus injection in mice, CI-941 induced dose-dependent leukopenia. The white blood cell counts were suppressed on day 3 by 18%, 50% and 65% of control, at doses of 10, 15 and 20 mg/kg CI-941, respectively. Other toxicities such as weight loss, alopecia, diarrhoea and convulsions were observed at doses >20 mg/kg. Lethality studies in female Balb-c mice resulted in an LD₁₀ value of 20 mg/kg (95% confidence limits; range, 19–21 mg/kg) and an LD₅₀ value of 22 mg/kg (95% confidence limits; range, 21–23 mg/kg). The pharmacokinetics of CI-941 were studied at four dose levels from 1/10 of the LD₁₀ to the LD₁₀ (20 mg/kg). The drug was rapidly cleared from the plasma (250–400 ml/min per kg) at a rate approaching the cardiac output of mice, displaying triphasic plasma pharmacokinetics. The area under the plasma CI-941 concentration vs time curve (AUC) was linear with respect to the dose, up to and including 15 mg/kg (AUC=110 M x min at 15 mg/kg), but became non-linear at 20 mg/kg (AUC=277 M x min). Despite 80%–84% plasma protein binding, CI-941 was rapidly and extensively distributed into tissues, especially the kidney. Following i.v. bolus injections at doses of 1.5 and 15 mg/kg, elimination of the parent compound by urinary excretion accounted for 12%–18% of the delivered dose. A phase-I starting dose (based on that equivalent to 1/10 of the LD₁₀ in the mouse) of 5 mg/m² CI-941 is recommended for single administration schedules. In addition, a pharmacokinetically guided dose-escalation strategy, based on achieving a target AUC of 110 M x min, is proposed.     

Phase I and pharmacokinetic study of weekly NV06 (Phenoxodiol™), a novel isoflav-3-ene, in patients with advanced cancer

Background: We wished to define the maximum tolerated dose (MTD), toxicity, and pharmacokinetics of the novel isoflav-3-ene, NV06 (Phenoxodiol™), a compound with a diphenolic structure related chemically and biologically to genistein and flavopiridol. Patients and Methods: Twenty-one patients with advanced cancers were treated with weekly intravenous administration of NV06 at escalating dose levels with 1–4 patients at each dose cohort. Plasma sampling was undertaken to characterize the pharmacokinetic (PK) profile of the compound. Results: Toxicity was minimal, with asymptomatic Grade 3 lymphocytopenia occurring in nine patients. Nine patients developed Grade 1 nausea, six patients developed Grade 1 increases in alkaline phosphatase, and six patients developed Grade 1 increases in transaminases. Two patients experienced hypersensitivity reactions. The MTD was not reached. Most patients had progressive disease on treatment but eight completed 12 weeks and two completed 24 weeks of treatment. The best response was stable disease of 6 months duration. The plasma half-life (T1/2), clearance (Cl), and volume of distribution (V _D) were 304 (±91) min, 82 (±19) ml/min and 32,663 (±7,199) ml, respectively, for total NV06. Conclusions: NV06 is well tolerated and can be given safely as an intravenous infusion over 1–2 h at a dose of at least 30 mg/kg.     

Phase 1 pharmacokinetic study of MK-0646 (dalotuzumab), an anti-insulin-like growth factor-1 receptor monoclonal antibody, in combination with cetuximab and irinotecan in Japanese patients with advanced colorectal cancer

Purpose

The safety, tolerability, and pharmacokinetic (PK) interactions of MK-0646 in combination with cetuximab and irinotecan were investigated in Japanese patients with advanced colorectal cancer.

Methods

Twenty patients were treated in the following study arms in combination with cetuximab and irinotecan: A [MK-0646 (10 mg/kg) weekly starting on Day 22], B [MK-0646 (15 mg/kg) on Day 8, followed by 7.5 mg/kg every 2 weeks], or C [MK-0646 (10 mg/kg) on Day 1 and weekly starting on Day 22]. Dose limiting toxicities (DLTs) were evaluated during a prespecified 4-week period in arms A and B. Full PK sampling was performed to evaluate the PK interactions.

Results

One of the 6 evaluable patients in arm A developed a DLT (grade 3 hyperglycemia); no DLTs occurred in the 6 patients in arm B. Common treatment-related adverse events included leukopenia, neutropenia, dermatitis acneiform, paronychia, nausea, stomatitis, diarrhea, and decreased appetite. The co-administration of cetuximab and irinotecan with MK-0646 increased the MK-0646 AUC_0–168h by 25 %, with MK-0646 accumulation from the previous dose contributing to the observed increase. The co-administration of MK-0646 with cetuximab and irinotecan did not affect the PK of cetuximab and irinotecan, but reduced the C _max (from 16.8 to 13.0 ng/mL) and the AUC_0–24h (by 13 %) of SN-38, the active metabolite of irinotecan.

Conclusions

The triple combination of MK-0646, cetuximab, and irinotecan was well tolerated in Japanese patients with advanced colorectal cancer. These results indicate a minimal potential for PK interactions between MK-0646 and cetuximab and between MK-0646 and irinotecan/SN-38.     

Pharmacokinetic and dose-finding study of osimertinib in patients with impaired renal function and low body weight

The safety of osimertinib is limited in patients with severe or moderate renal impairment, or low body weight. This study aimed to investigate the safety, pharmacokinetics (PK) and recommended dose (RD) of osimertinib in patients with epidermal growth factor receptor (EGFR)-mutated non–small cell lung cancer (NSCLC) with impaired renal function and low body weight. Thirty-one eligible patients were enrolled and allocated into four cohorts: A, normal renal function (estimated glomerular filtration rate [eGFR] ≥ 50 mL/min/1.73 m²) and normal body weight (≥45 kg); B, moderate renal impairment (eGFR = 30-50 mL/min/1.73 m²); C, low body weight (<45 kg); and D, severe renal impairment (eGFR <30 mL/min/1.73 m² or undergoing dialysis). PK parameters and safety were evaluated with a starting dose of 80 mg osimertinib administered orally once daily in cohorts A, B, and C and 40 mg once daily in cohort D. The PK parameters in cohorts A, B, and C were found to be similar. No dose-limiting toxicity was observed, and the RD was determined to be 80 mg once daily in patients with moderate renal function and low body weight. Four serious adverse events, acneiform rash, diarrhea, QTc prolongation, and interstitial lung disease, were noted. Although the PK parameters of osimertinib were similar across all cohorts, toxicity occurred more frequently in patients with impaired renal function and low body weight. Clinicians should prescribe osimertinib with caution in NSCLC patients with impaired renal function and low body weight.     

Estrogen suppression in premenopausal women following 8 weeks of treatment with exemestane and triptorelin versus triptorelin alone

Introduction Luteinizing hormone-releasing hormone (LHRH) agonists (e.g., triptorelin) reduce ovarian estrogen production in premenopausal women with hormone-sensitive breast cancer. Aromatase inhibitors (e.g., exemestane) inhibit extraovarian production of estrogen and may further reduce circulating estrogens when combined with an LHRH agonist. Methods Healthy premenopausal women were randomized to receive 3.75 mg triptorelin (T) on days 1 and 29 with 25 mg exemestane (EX) or matched placebo once daily for 8 weeks, from day 1 to day 56. The primary objective was to evaluate the effect of T ± EX on estradiol (E₂) suppression by comparing the AUC_day36–57 for the 2 treatments. Secondary objectives included evaluation of estrone (E₁), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) suppression; effects of EX on the T-induced gonadotrophin and estrogen flare; pharmacokinetics (PK); and safety. Results Twenty-eight (14 in each arm) were evaluable for efficacy and PK. Mean plasma estrogen levels (AUC_day36–57) were significantly lower for subjects who received T + EX than for subjects who received T alone (20.6 vs. 54.0 pg d/ml [−62%; P < 0.05], and 38.9 vs. 198.0 pg d/ml [−80%; P < 0.01] for E₂ and E₁, respectively). Coadministration of EX did not affect the initial flare or subsequent suppression of LH and FSH following the first dose of T, or the PK of T. Both treatments were well tolerated. Conclusions Coadministration of T and EX resulted in greater estrogen suppression than when T was given alone. These findings could translate into improved clinical outcomes for premenopausal breast cancer patients receiving LHRH agonists.