13C-uracil breath test to predict 5-fluorouracil toxicity in gastrointestinal cancer patients

Purpose

Up to 30 % of patients undergoing 5-fluorouracil (5FU)-based chemotherapy experience severe toxicity. Dihydropyrimidine dehydrogenase (DPD) deficiency explains 36–61 % of cases. Predicting toxicity is an unmet challenge. Uracil breath test (UraBT) consists of measuring ¹³CO₂ in exhaled breath after ingestion of 2-¹³C-uracil to evaluate pyrimidine (and 5FU) catabolism.

Methods

We studied 33 gastrointestinal cancer patients previously exposed to 5FU: Thirteen had grade 3–4 and 20, grade 0–1 toxicity. The following tests were used to evaluate pyrimidine catabolism: (1) sequencing of three exons of DPYD; (2) plasma dihydrouracil/uracil ratio (UH₂/U); and (3) UraBT. We tested the performance of UraBT to discriminate patients who had grade 0–1 toxicity versus grade 3–4 toxicity and patients with and without proven DPD deficiency.

Results

Of the thirteen patients, four grade 3–4 toxicity patients were proved to be DPD-deficient: Three had deleterious mutations (IVS14 + 1G>A in one; single nucleotide polymorphism 2846A>T in two), and one had low UH₂/U ratio. Mean delta over baseline in 50 min (DOB₅₀) significantly differed between groups. DOB₅₀≤161.4 discriminated individuals with grade 3–4 versus grade 0–1 toxicity (sensitivity = 61.5 %; specificity = 85 %) and DPD-deficient versus non-DPD-deficient (sensitivity = 75 %; specificity = 85 %).

Conclusion

UraBT has moderate accuracy in discriminating individuals who manifested severe toxicity from those who had mild or no toxicity to 5FU.     

Evaluation of pharmacokinetics and safety of ponatinib in subjects with chronic hepatic impairment and matched healthy subjects

Purpose

This study evaluated the effects of chronic hepatic impairment on the single-dose pharmacokinetics (PK) of the tyrosine kinase inhibitor ponatinib.

Methods

Subjects (n = 16) had Child-Pugh class A (mild, n = 6), B (moderate, n = 6), or C (severe, n = 4) hepatic impairment and were matched with healthy controls (n = 8). Each subject received a single oral dose of ponatinib 30 mg under fasting conditions, and PK parameters were assessed in blood samples collected through 96 h post-dose.

Results

Ponatinib maximum plasma concentrations (C _max) were observed after 5–6 h in Child-Pugh A, Child-Pugh B, and healthy subjects, and after ~3 h in Child-Pugh C subjects. The estimated  % geometric mean ratios for C _max, area under the plasma concentration–time curves from time zero to last observation (AUC_0–t ) and to infinity (AUC_0–∞) suggested a slightly lower exposure in Child-Pugh B (61.4, 89.1, and 90.6 %, respectively) and Child-Pugh C subjects (62.8, 77.1, and 79.4 %) versus healthy subjects. Child-Pugh A subjects had similar estimated % geometric mean ratio for C _max (106.7 %), and slightly greater estimated % geometric mean ratios for AUC_0–t (133.0 %) and AUC_0–∞ (122.8 %), versus healthy subjects. Mean elimination half-life was extended in subjects with hepatic impairment (43–47 vs 36 h). Ponatinib was generally well tolerated. A single serious AE (pancreatitis) in the Child-Pugh C group resolved with treatment.

Discussion

As no major differences in ponatinib single-dose PK were observed in patients with hepatic impairment versus healthy subjects, a reduction of ponatinib starting dose in these patients is not necessary, but caution is recommended when administering ponatinib to these patients.     

Population pharmacokinetics of peritoneal,plasma ultrafiltrated and protein-bound oxaliplatin concentrations in patients with disseminated peritoneal cancer after intraperitoneal hyperthermic chemoperfusion of oxaliplatin following cytoreductive surgery: correlation between oxaliplatin exposure and thrombocytopenia

Purpose

First, to evaluate the peritoneal (IP), plasma ultrafiltrated (UF) and protein-bound (B) pharmacokinetics (PK) of oxaliplatin after intraperitoneal hyperthermic chemoperfusion (HIPEC) following cytoreductive surgery. Second, to evaluate the relationship between oxaliplatin exposure and observed toxicity.

Methods

IP, UF, and B concentrations from 75 patients treated by 30-min oxaliplatin-based HIPEC procedures were analysed according to a pharmacokinetic modelling approach using NONMEM. Oxaliplatin was administered in a 5 % dextrose solution (2 L/m²) at 360 (n = 58) or 460 mg/m² (n = 17). The most frequently observed toxicities were related to the peritoneal, systemic exposures and to the parameters corresponding to the oxaliplatin absorption from peritoneal cavity into plasma.

Results

IP (n = 536), UF (n = 669) and B (n = 661) concentrations were simultaneously described according to a five-compartment PK model with irreversible nonlinear binding from UF to B according to a Michaelis–Menten equation. The mean (±SD) maximum fraction of dose absorbed and elimination half-life from the peritoneum was 53.7 % (±8.5) and 0.49 h (±0.1), respectively. The mean (±SD) ratio AUC_IP/AUC_UF was 5.3 (±2) confirming the pharmacokinetic advantage of the procedure. Haemoperitoneum (22.7 %), neuropathy (18.7 %), grade 3/4 thrombocytopenia (13.3 %) were the most frequently reported toxicities. AUC_UF accounts for approximately 12 % of the variation in the maximum percentage of platelet decrease (r = 0.35, p = 0.002). Thrombocytopenia was correlated with higher AUC_UF, partly dependent on the extent and rate of oxaliplatin absorption.

Conclusions

Despite a common dose administered, variability in peritoneal and systemic oxaliplatin exposures are observed, leading to differences in haematological toxicity between patients.     

Phase 1 first-in-human clinical study of S-trans, trans-farnesylthiosalicylic acid (salirasib) in patients with solid tumors

Purpose

This phase I first-in-human trial evaluated salirasib, an S-prenyl derivative of thiosalicylic acid that competitively blocks RAS signaling.

Methods

Patients with advanced cancers received salirasib twice daily for 21 days every 4 weeks. Doses were escalated from 100 to 200, 400, 600, and 800 mg.

Results

The most common toxicity was dose-related diarrhea (Grade 1–2, 79% of 24 patients). Other toxicities included abdominal pain, nausea, and vomiting. No Grade 3–4 toxicity was noted. Nineteen (79%) patients had no drug-related toxicity >Grade 1. Dose-limiting toxicity (DLT) was not reached, but all three patients treated with 800 mg experienced Grade 1–2 diarrhea, abrogating dose escalation. Six patients were treated at a dose of 600 mg with no DLTs. Seven (29%) patients had stable disease on salirasib for ≥4 months (range 4–23+). The salirasib pharmacokinetic profile was characterized by slow absorption and a rapid elimination phase following oral administration. Salirasib exposure (C _max; day 1 AUC_inf vs. day 15 AUC_0–12 h) was similar between days 1 and 15 (P > 0.05). The T _1/2 (mean ± SD) was 3.6 ± 2.2 h on day 1.

Conclusions

Salirasib therapy was well tolerated. The recommended dose for phase II studies is 600 mg twice daily.     

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.     

Pharmacokinetics of orally administered ABT-751 in children with neuroblastoma and other solid tumors

Purpose

To describe the pharmacokinetics of orally administered ABT-751 and its conjugated metabolites in children with neuroblastoma and other solid tumors and to relate pharmacokinetic parameters to toxicity and therapeutic outcomes.

Methods

Patients (median age, 11 years) with neuroblastoma (n = 37) or other solid tumors (n = 25) had pharmacokinetic sampling after the first dose of ABT-751 (75–250 mg/m²/day) on a 7-day or 21-day schedule. ABT-751 and its glucuronide and sulfate metabolites were quantified with an HPLC/MS/MS assay. Pharmacokinetic parameters were derived with non-compartmental methods. The relative bioavailability of more water soluble capsule and suspension formulations was assessed.

Results

ABT-751 peaked in plasma at 2 h and declined monoexponentially with a t _1/2 of 5.1 h. The apparent clearance was 33 ml/min/m² and was age-independent. The AUC_0–∞ increased in proportion to the dose, and at 200 mg/m² the median AUC_0–∞ was 91 mcg h/ml and the C _ave was 3.9 mcg/ml. Inter-and intra-patient variability was low. The metabolites were detected in plasma 30 min post-dose and peaked 3–5 h after the dose. The glucuronide:sulfate molar AUC_0–∞ ratio was 0.57. Less than 1% of the dose was excreted in urine as parent drug; 13% of the dose was excreted as sulfate metabolite and 10% as glucuronide metabolite. The relative bioavailability of the water soluble capsule and suspension formulations was 105 and 93%, respectively. AUC_0–∞ was higher in patients experiencing dose-limiting toxicity.

Conclusions

Oral ABT-751 pharmacokinetics was dose-proportional and age-independent with minimal intra- and inter-patient variability in children.     

The contribution of deleterious DPYD gene sequence variants to fluoropyrimidine toxicity in British cancer patients

Purpose

The fluoropyrimidines have been extensively used for almost five decade worldwide for the treatment of solid cancers. However, severe toxicity is a major clinical problem and has been reported in association with deleterious sequence variants in dihydropyrimidine dehydrogenase (DPD) coding-gene (DPYD), causing DPD deficiency. Genetic DPD deficiency has previously been considered to be insignificant in the British population. The study aim was to assess the contribution of deleterious DPYD sequence variants to fluoropyrimidine toxicity amongst British cancer patients.

Methods

Sequencing of the coding region of DPYD was undertaken in 47 patients (27 female, mean age 61 years), mainly with GI malignancy, experiencing grade 3 or 4 toxicity on fluoropyrimidines according to CTCAE criteria.

Results

Myelotoxicity (37.5%) and diarrhoea (37.5%) were the most frequent toxicities followed by mucositis (19.6%), hand–foot syndrome (3.6%) and neurotoxicity (1.8%). 4 of 47 (8.5%) patients carried the 1905+1G>A splice site variant. All 4 cases were female and 3 of 4 suffered severe diarrhoea. A further five cases carried other sequence variants (2846A>T n = 4, 1679T>G n = 1). In total, 9 (19%) patients carried deficiency associated DPYD sequence variants.

Conclusions

Contrary to previous estimates for a UK population, genetic DPD deficiency accounts for around 19% of cases of severe fluoropyrimidine toxicity. The influence of DPD deficiency is such that toxicity can be avoided by prior testing and appropriate 5-FU dose/regimen alteration.     

Effects of ketoconazole and esomeprazole on the pharmacokinetics of pazopanib in patients with solid tumors

Purpose

The metabolism of pazopanib is primarily mediated by CYP3A4. The solubility of pazopanib is pH-dependent, and an elevated gastric pH may decrease its bioavailability. This study evaluated the effect of a potent CYP3A4 inhibitor, ketoconazole, and the proton pump inhibitor esomeprazole on the pharmacokinetics and safety of pazopanib and its metabolites.

Methods

In Arm A, patients received pazopanib 400 mg alone once daily for 7 days followed by pazopanib 400 mg plus ketoconazole 400 mg once daily for 5 days. In Arm B, patients received pazopanib 800 mg once daily for 7 days, followed by pazopanib 800 mg plus esomeprazole 40 mg once daily for 5 days, and then pazopanib alone on the last day.

Results

Arm A enrolled 21 patients. In the presence of ketoconazole, mean area under the plasma concentration–time curve 24 h post-dose (AUC_(0–24)) and mean maximum observed concentration (C _max) of pazopanib increased by 66 and 45 %, respectively; mean AUC_(0–24) and C _max for pazopanib metabolites were lower or remained unchanged. Arm B enrolled 13 patients. In the presence of esomeprazole, mean pazopanib AUC_(0–24) and C _max decreased by 40 and 42 %, respectively; mean values of those parameters for metabolites of pazopanib also decreased.

Conclusions

Concomitant use of pazopanib with a strong CYP3A4 inhibitor should be avoided. If coadministration is necessary, pazopanib should be reduced to 400 mg. Concomitant use of pazopanib and proton pump inhibitors should also be avoided. Alternative dosing regimens that do not increase gastric pH at the time of pazopanib dosing should be considered.     

A phase I, randomized, open-label study of the multiple-dose pharmacokinetics of vemurafenib in patients with BRAF V600E mutation-positive metastatic melanoma

Purpose

This study characterized the multiple-dose pharmacokinetics of vemurafenib 240–960 mg twice daily (bid) in BRAF ^V600E mutation-positive metastatic melanoma patients, using the commercial formulation (240-mg microprecipitated bulk powder film-coated tablets).

Methods

Melanoma patients (N = 52) were randomly allocated to four vemurafenib dose cohorts (240, 480, 720, or 960 mg bid for 14 days). After the day 15 morning dose, doses were interrupted until day 22, at which point patients were restarted on vemurafenib. Serial pharmacokinetic samples were collected after the morning dose on days 1, 9, and 15; trough pharmacokinetic samples were collected on day 2.

Results

Vemurafenib concentration increased with multiple doses to steady state at day 15; C _max, AUC_0–8h, and AUC_0–168h increased between 3.3- and 3.8-fold across the fourfold dose range tested. Statistical analysis indicated dose proportionality across the dose range of 240–960 mg bid. Day 15 mean accumulation ratios (ratio of AUC_0–8h on day 15/AUC_0–8h on day 1) ranged from ~19 to 25 across cohorts. At steady state, the peak-to-trough ratio for vemurafenib exhibited a relatively flat concentration–time profile throughout the bid dosing interval. During dose interruption (days 15–22), mean vemurafenib trough concentrations decreased to minimal levels; vemurafenib exhibited a mean terminal phase half-life of 31.5–38.4 h.

Conclusions

Vemurafenib plasma concentration accumulates with multiple bid doses of 240 mg. Vemurafenib exposure (AUC and C _max) is dose proportional over the 240- to 960-mg bid dose range and exhibits constant drug levels over the bid dosing interval.     

Effects of famotidine or an antacid preparation on the pharmacokinetics of nilotinib in healthy volunteers

Purpose

This study evaluated the effects of either famotidine or antacid on the pharmacokinetics of nilotinib in healthy subjects, with the specific focus to explore different dosing separation schemes leading to a minimized drug–drug interaction.

Methods

Fifty-two subjects were randomized to receive the following treatments in a crossover manner: (A) single oral nilotinib 400 mg alone; (B) famotidine 20 mg twice a day for 3 days, followed by a single administration of nilotinib 400 mg and famotidine 20 mg on Day 4, where famotidine was given 2 h after nilotinib; (C) single oral nilotinib 400 mg and antacid suspension 20 mL, where antacid was given 2 h before nilotinib; (D) single oral nilotinib 400 mg and antacid suspension 20 mL, where antacid was given 2 h after nilotinib.

Results

Comparing Treatment B to Treatment A, the geometric mean ratios of nilotinib C _max, AUC_0-tlast, and AUC_0-inf were 0.966, 0.984, and 0.911, respectively (90 % confidence intervals (CIs), 0.875–1.066, 0.905–1.069, and 0.798–1.039, respectively). Nilotinib pharmacokinetic parameters following Treatment C or Treatment D were similar to those after Treatment A; the corresponding 90 % CIs of the geometric mean ratios of C _max, AUC_0-tlast, and AUC_0-inf all fell within the bioequivalence range of 0.8–1.25.

Conclusions

Neither famotidine nor antacid significantly affected nilotinib pharmacokinetics. When concurrent use of an H2 blocker or an antacid is necessary, the H2 blocker may be administered 10 h before and 2 h after nilotinib dose, or the antacid may be administered 2 h before or 2 h after nilotinib dose.     

The effect of formulation and food consumption on the bioavailability of dovitinib (TKI258) in patients with advanced solid tumors

Purpose

This 2-arm, phase 1, crossover study compared the relative bioavailability of two dovitinib (TKI258) capsule formulations [anhydrate clinical service form (CSF) and monohydrate final market image (FMI); Arm 1] and determined the effect of food on dovitinib exposure (Arm 2).

Methods

Patients with advanced solid tumors were enrolled in one of the 2 arms. Arm 1 randomized patients to a single 500-mg dose of either CSF or FMI followed by 7 days of rest and 500 mg of the other formulation. Arm 2 patients received 300 mg of FMI once daily and were randomized to follow one of six meal sequences, each with three prandial conditions: low fat (LF), high fat (HF), or no meal (NM).

Results

Twenty-three and 37 patients were enrolled and 19 and 21 were evaluable in Arms 1 and 2, respectively. In Arm 1, the adjusted geometric means for FMI had small reductions relative to CSF [area under the plasma concentration–time curve (AUC_last) decreased by 12 %, maximum concentration (C _max) decreased by 3 %]. In Arm 2, the HF meal versus NM showed a 2 % increase in the adjusted geometric mean for AUC_last and a 5 % decrease for C _max. The LF meal versus NM comparison showed 9 and 6 % increases for AUC_last and C _max, respectively. Overall, common adverse events included nausea, vomiting, diarrhea, and fatigue.

Conclusions

Systemic exposure to dovitinib was similar for the FMI and CSF capsule formulations. Additionally, since prandial conditions did not affect the systemic exposure, dovitinib can be taken with or without food.     

Co-administration of vismodegib with rosiglitazone or combined oral contraceptive in patients with locally advanced or metastatic solid tumors: a pharmacokinetic assessment of drug–drug interaction potential

Purpose

Vismodegib, a first-in-class oral hedgehog pathway inhibitor, is an effective treatment for advanced basal cell carcinoma. Based on in vitro data, a clinical drug–drug interaction (DDI) assessment of cytochrome P450 (CYP) 2C8 was necessary; vismodegib’s teratogenic potential warranted a DDI study with oral contraceptives (OCs).

Methods

This single-arm, open-label study included two cohorts of patients with locally advanced or metastatic solid malignancies [Cohort 1: rosiglitazone 4 mg (selective CYP2C8 probe); Cohort 2: OC (norethindrone 1 mg/ethinyl estradiol 35 μg; CYP3A4 substrate)]. On Day 1, patients received rosiglitazone or OC. On Days 2–7, patients received vismodegib 150 mg/day. On Day 8, patients received vismodegib plus rosiglitazone or OC. The effect of vismodegib on rosiglitazone and OC pharmacokinetic parameters (primary objective) was evaluated through pharmacokinetic sampling over a 24-h period (Days 1 and 8).

Results

The mean ± SD vismodegib steady-state plasma concentration (Day 8, N = 51) was 20.6 ± 9.72 μM (range 7.93–62.4 μM). Rosiglitazone AUC_0–inf and C _max were similar with concomitant vismodegib [≤8 % change in geometric mean ratios (GMRs); N = 24]. Concomitant vismodegib with OC did not affect ethinyl estradiol AUC_0–inf and C _max (≤5 % change in GMRs; N = 27); norethindrone C _max and AUC_0–inf GMRs were higher (12 and 23 %, respectively) with concomitant vismodegib.

Conclusions

This DDI study in patients with cancer demonstrated that systemic exposure of rosiglitazone (a CYP2C8 substrate) or OC (ethinyl estradiol/norethindrone) is not altered with concomitant vismodegib. Overall, there appears to be a low potential for DDIs when vismodegib is co-administered with other medications.     

The effect of rifampicin,a prototypical CYP3A4 inducer,on erlotinib pharmacokinetics in healthy subjects

Purpose

Erlotinib, N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy) quinazolin-4-amine is approved for the treatment for non-small cell lung cancer and pancreatic cancer. Because erlotinib is metabolized predominately by CYP3A4, co-administration of compounds that increase CYP3A4 activity may alter the efficacy and safety of erlotinib therapy. Two phase I studies were conducted in healthy male subjects to evaluate the effect of pre- or co-administered rifampicin, a CYP3A4 inducer, on the pharmacokinetics of erlotinib.

Methods

Study 1 included Groups A (erlotinib 150 mg days 1 and 15, rifampicin 600 mg days 8–14) and B (erlotinib 150 mg days 1 and 15) in a parallel group study design. Study 2 subjects received erlotinib 150 mg day 1, erlotinib 450 mg day 15, and rifampicin 600 mg days 8–18. The primary endpoint in each study was the ratio of exposure (AUC_0–∞ and C _max) between days 1 and 15. Urinary cortisol metabolic induction ratios were determined in Study 1 for Group A subjects only.

Results

In Study 1, the geometric mean ratios of AUC_0–∞ and C _max were 33 and 71 %, respectively, and the mean cortisol metabolic index increased from 7.4 to 27.0, suggesting cytochrome P450 (CYP) enzyme induction. In Study 2, the geometric mean ratios for AUC_0–∞ and C _max were 19 and 34 % (when dose adjusted from 450 to 150 mg erlotinib), respectively, a greater relative decrease than observed in Study 1.

Conclusions

Erlotinib exposure (AUC_0–∞ and C _max) was reduced after pre- or concomitant dosing with rifampicin. Doses of ≥450 mg erlotinib may be necessary to compensate for concomitant medications with strong CYP3A4 enzyme induction effect.     

Microdialysis measurement of intratumoral temozolomide concentration after cediranib, a pan-VEGF receptor tyrosine kinase inhibitor, in a U87 glioma model

Background

Combining anti-angiogenesis agents with cytotoxic agents for the treatment of malignant gliomas may affect the cytotoxic drug distribution by normalizing the blood–brain barrier (BBB). This study examines the intratumoral concentration of temozolomide (TMZ) in the presence and absence of the pan-VEGF receptor tyrosine kinase inhibitor, cediranib.

Methods

Seven nude rats bearing U87 intracerebral gliomas had a microdialysis probe centered within the tumor. Ten-days after tumor implantation, TMZ (50 mg/kg) was given orally. The extracellular fluid (ECF) concentrations of TMZ within the tumor were assessed via microdialysis for 6 h following TMZ administration. Cediranib (6 mg/kg) was then given orally, and 12 h later, TMZ was re-administered with subsequent microdialysis collection. A subset of animals also underwent functional MRI to assess angiogenesis in vivo at post-inoculation days 12 and 21, before and after the cediranib treatment.

Results

After dosing of oral TMZ only, ECF-TMZ mean-C _max and area under the concentration curve(AUC_0–∞) within the tumor were 0.59 μg/mL and 1.82 μg h/mL, respectively. Post-cediranib, ECF-TMZ mean-C _max and AUC_0–∞ were 0.83 μg/mL and 3.72 ± 0.61 μg h/mL within the tumor, respectively. This represented a 1.4-fold (p = 0.3) and 2.0-fold (p = 0.06) increase in the ECF-TMZ C _max and AUC_0–∞, respectively, after cediranib administration. In vivo MRI measurements of the various vascular parameters were consistent with a BBB “normalization” profile following cediranib treatment.

Conclusions

In the U87 intracerebral glioma model, within the first day of administration of cediranib, the intratumoral concentrations of TMZ in tumor ECF were slightly, but not statistically significantly, increased when compared to the treatment of TMZ alone with radiographic evidence of a normalized BBB.     

Population pharmacokinetic analysis of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) in adult patients with solid tumors

Purpose

To identify sources of exposure variability for the tumor growth inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) using a population pharmacokinetic analysis.

Methods

A total 67 solid tumor patients at 2 centers were given 1 h infusions of 17-DMAG either as a single dose, daily for 3 days, or daily for 5 days. Blood samples were extensively collected and 17-DMAG plasma concentrations were measured by liquid chromatography/mass spectrometry. Population pharmacokinetic analysis of the 17-DMAG plasma concentration with time was performed using nonlinear mixed effect modeling to evaluate the effects of covariates, inter-individual variability, and between-occasion variability on model parameters using a stepwise forward addition then backward elimination modeling approach. The inter-individual exposure variability and the effects of between-occasion variability on exposure were assessed by simulating the 95 % prediction interval of the AUC per dose, AUC_0–24 h, using the final model and a model with no between-occasion variability, respectively, subject to the five day 17-DMAG infusion protocol with administrations of the median observed dose.

Results

A 3-compartment model with first order elimination (ADVAN11, TRANS4) and a proportional residual error, exponentiated inter-individual variability and between occasion variability on Q2 and V1 best described the 17-DMAG concentration data. No covariates were statistically significant. The simulated 95% prediction interval of the AUC_0–24 h for the median dose of 36 mg/m² was 1,059–9,007 mg/L h and the simulated 95 % prediction interval of the AUC_0–24 h considering the impact of between-occasion variability alone was 2,910–4,077 mg/L h.

Conclusions

Population pharmacokinetic analysis of 17-DMAG found no significant covariate effects and considerable inter-individual variability; this implies a wide range of exposures in the population and which may affect treatment outcome. Patients treated with 17-DMAG may require therapeutic drug monitoring which could help achieve more uniform exposure leading to safer and more effective therapy.     

Midazolam as a phenotyping probe to predict sunitinib exposure in patients with cancer

Purpose

Patients treated with sunitinib show substantial inter-patient variability in drug exposure (~30–40 %), which is largely unexplained. Since sunitinib is metabolized by cytochrome P450(CYP)3A4, variability in the activity of this enzyme may explain a considerable proportion of this inter-patient variability. Midazolam is widely used as a phenotyping probe to assess CYP3A4-activity. The objective of this study was to prospectively evaluate the relationship between midazolam and sunitinib exposure. Additionally, the correlation between sunitinib trough levels and exposure and the influence of sunitinib on midazolam exposure was determined.

Methods

Thirteen patients treated with sunitinib in a 4 weeks “on”—2 weeks “off” regimen received twice 7.5 mg midazolam; once with and once without sunitinib. Steady-state sunitinib, its active metabolite SU12662 and midazolam exposures were determined.

Results

A significant correlation between midazolam exposure (AUC_0–7h) and steady-state sunitinib and sunitinib + SU12662 exposure (AUC_0–24h) was found (p = 0.006 and p = 0.0018, respectively); midazolam exposure explained 51 and 41 % of the inter-patient variability in sunitinib and sunitinib + SU12622 exposure. Furthermore, C _trough was highly correlated (r ² = 0.94) with sunitinib AUC_0–24h. Sunitinib decreased midazolam exposure with 24 % (p = 0.034).

Conclusion

Midazolam exposure is highly correlated with sunitinib exposure and explains a large proportion of the observed inter-patient variability in sunitinib pharmacokinetics. Consequently, midazolam could be used to identify patients that are at risk of under- or overtreatment, respectively, at the start of sunitinib therapy. Moreover, sunitinib and sunitinib + SU12662 trough levels are highly correlated with drug exposure and can thus be used in clinical practice to individualize sunitinib therapy. The decrease in midazolam exposure by sunitinib needs further investigation.     

Pharmacokinetics of afatinib in subjects with mild or moderate hepatic impairment

Purpose

Afatinib, an oral irreversible ErbB family blocker, undergoes minimal metabolism by non-enzyme-catalysed adduct formation with proteins or nucleophilic small molecules and is predominantly non-renally excreted via the entero-hepatic system. This trial assessed whether mild or moderate hepatic impairment influences the pharmacokinetics of afatinib.

Methods

This was an open-label single-dose study. Pharmacokinetic parameters after afatinib 50 mg were investigated in subjects with mild (n = 8) or moderate (n = 8) hepatic impairment (Child-Pugh A and B) and healthy controls (n = 16) matched for age, weight and gender. Plasma and urine samples for pharmacokinetic assessment were collected before and up to 10 days after dosing. Additional blood samples were drawn to determine ex vivo plasma protein binding of afatinib. Primary endpoints were comparisons of afatinib C _max and AUC_0–∞ between subjects with hepatic impairment and healthy matched controls. Study progression was based on drug-related toxicity (CTCAE v. 3.0) and C _max of afatinib.

Results

Afatinib pharmacokinetic profiles and plasma protein binding were similar in subjects with impaired liver function and healthy controls. Compared with matched controls, the afatinib-adjusted geometric mean ratio for AUC_0–∞ was 92.6 % (90 % CI 68.0–126.3 %) and C _max was 109.5 % (90 % CI 82.7–144.9 %) for subjects with mild hepatic impairment, and 94.9 % (90 % CI 72.3–124.5 %) and 126.9 % (90 % CI 86.0–187.2 %), respectively, for subjects with moderate hepatic impairment. For all parameters, the 90 % CI included 100 %. Afatinib was generally well tolerated with no serious adverse events reported.

Conclusion

Mild to moderate hepatic impairment had no clinically relevant effect on the pharmacokinetics of a single 50 mg dose of afatinib, implying that adjustments to the starting dose of afatinib are not considered necessary in this patient population.     

Effect of rifampin on the pharmacokinetics of Axitinib (AG-013736) in Japanese and Caucasian healthy volunteers

Purpose

Axitinib, a potent and selective inhibitor of vascular endothelial growth factor receptors 1, 2, 3, is metabolized by cytochrome P450 3A4 and glucuronidation. This study evaluated the effect of rifampin, a potent inducer of drug-metabolizing enzymes, on axitinib plasma pharmacokinetics. Equal numbers of Japanese and Caucasian subjects were enrolled to assess the potential differences in axitinib pharmacokinetics between the two ethnicities.

Methods

Forty healthy volunteers were randomized to receive 5 mg axitinib alone and with 600 mg rifampin.

Results

Rifampin expectedly decreased AUC_inf and C _max of axitinib (geometric mean reduced by 79 and 71%, respectively). However, differences in axitinib pharmacokinetics were not observed between Japanese and Caucasian subjects (geometric mean ratios for axitinib treatment alone for AUC_inf and C _max were 103 and 96%).

Conclusions

The results support a common axitinib starting dose in both populations. Potent inducers of drug-metabolizing enzymes reduce axitinib exposure and dose adjustments may be needed for optimal efficacy.     

Comparative pharmacokinetics of subcutaneous trastuzumab administered via handheld syringe or proprietary single-use injection device in healthy males

Purpose

To demonstrate pharmacokinetic (PK) comparability for a single dose of 600 mg subcutaneous (SC) trastuzumab, administered via a novel single-use injection device (SID) or handheld syringe in 119 randomized healthy male subjects.

Methods

The co-primary PK endpoints area under the time–concentration curve from the start of dosing to day 22 (AUC_0–21 days) and maximum observed trastuzumab serum concentration (C _max) were dose-normalized and body-weight-adjusted, and compared using geometric mean ratios (GMRs). SID performance, injection site pain, adverse events, and antidrug antibodies (ADAs) were assessed.

Results

GMRs and 90 % confidence intervals (CIs) were 1.01 (0.96–1.07) for AUC_0–21 days and 1.02 (0.96–1.10) for C _max, which fell within the prespecified bioequivalence range (0.80–1.25). No SID quality issues or failures occurred. Adverse events were mostly mild, with no deaths, adverse event-related withdrawals, or life-threatening, cardiac, or serious events reported. The ADA rate was low, and no neutralizing antibodies were detected.

Conclusions

Trastuzumab SC via SID demonstrated comparable PK and safety to handheld syringe administration. SID performance was very satisfactory.     

Comparison of pharmacokinetics and safety profiles of two capecitabine tablet formulations in patients with colon, colorectal or breast cancer

Purpose

The objective of this study was to compare the pharmacokinetics and safety of two tablet formulations containing 500 mg of capecitabine (CAS number 154361-50-9) in patients with colon, colorectal or breast cancer.

Methods

The study was a multicentric, open label, randomized, two-treatment, two-period, two-sequence, single dose, crossover bioequivalence study in patients of either sex with colon, colorectal or breast cancer. Eligible patients received each treatment in a crossover manner under fed conditions according to the randomization schedule. The pre-dose blood sample was taken within 90 min prior to dosing, and serial blood sampling was done up to 10.00 h post-dose under monochromatic light. The analysis of plasma samples for concentrations of capecitabine and 5′-deoxy-5-fluorocytidine (5′-DFCR) was carried out using a validated liquid chromatography mass spectrometry method. Bioequivalence was to be concluded if the confidence intervals so constructed were within the range of 80–125 % for C_max, AUC_0?t and AUC_0?∞ of capecitabine and 5′-DFCR. Patients were monitored for safety and tolerability throughout the study.

Results

The 90 % confidence intervals for the “test/reference” mean ratios of the ln-transformed pharmacokinetic variables C_max, AUC_0?t and AUC_0?∞ were clearly within the conventional bioequivalence range of 80–125 %. Both the formulations were reasonably tolerated after a single oral dose in patients.

Conclusions

Both the capecitabine tablet formulations demonstrated equivalent rate and extent of systemic absorption, and hence were considered bioequivalent. Therefore, the two formulations can be considered as equivalent in terms of pharmacokinetics and safety profiles.