Horst Schran

Clinical Pharmacokinetics of Imatinib

Imatinib is a potent and selective inhibitor of the protein tyrosine kinase Bcr-Abl, platelet-derived growth factor receptors (PDGFRα and PDGFRβ) and KIT. Imatinib is approved for the treatment of chronic myeloid leukaemia (CML) and gastrointestinal stromal tumour (GIST), which have dysregulated activity of an imatinib-sensitive kinase as the underlying pathogenetic feature.Pharmacokinetic studies of imatinib in healthy volunteers and patients with CML, GIST and other cancers show that orally administered imatinib is well absorbed, and has an absolute bioavailability of 98% irrespective of oral dosage form (solution, capsule, tablet) or dosage strength (100mg, 400mg). Food has no relevant impact on the rate or extent of bioavailability. The terminal elimination half-life is approximately 18 hours. Imatinib plasma concentrations predictably increase by 2- to 3-fold when reaching steady state with 400mg once-daily administration, to 2.6 ± 0.8 μg/mL at peak and 1.2 ± 0.8 μg/mL at trough, exceeding the 0.5 μg/mL (1 μmol/L) concentrations needed for tyrosine kinase inhibition in vitro and leading to normalisation of haematological parameters in the large majority of patients with CML irrespective of baseline white blood cell count.Imatinib is approximately 95% bound to human plasma proteins, mainly albumin and α1-acid glycoprotein. The drug is eliminated predominantly via the bile in the form of metabolites, one of which (CGP 74588) shows comparable pharmacological activity to the parent drug. The faecal to urinary excretion ratio is approximately 5:1.Imatinib is metabolised mainly by the cytochrome P450 (CYP) 3A4 or CYP3A5 and can competitively inhibit the metabolism of drugs that are CYP3A4 or CYP3A5 substrates. Interactions may occur between imatinib and inhibitors or inducers of these enzymes, leading to changes in the plasma concentration of imatinib as well as coadministered drugs.Hepatic and renal dysfunction, and the presence of liver metastases, may result in more variable and increased exposure to the drug, although typically not necessitating dosage adjustment. Age (range 18–70 years), race, sex and bodyweight do not appreciably impact the pharmacokinetics of imatinib.

Pharmacokinetics and Pharmacodynamics of Zoledronic Acid in Cancer Patients with Bone Metastases

The pharmacokinetics, pharmacodynamics, and safety of zoledronic acid (Zometa®), a new‐generation bisphosphonate, were evaluated in 36 patients with cancer and bone metastases. Zoledronic acid (by specific radioimmunoassay) and markers of bone turnover were determined in plasma and urine after three consecutive infusions (qx28 days) of 4 mg/5 min (n = 5), 4 mg/15 min (n = 7), 8 mg/15 min (n = 12), or 16 mg/15 min (n = 12). Zoledronic plasma disposition was multiphasic, with half‐lives of 0.2 and 1.4 hours representing an early, rapid decline of concentrations from the end‐of‐infusion Cmax to < 1% of Cmax at 24 hours postdose and half‐lives of 39 and 4526 hours describing subsequent phases of very low concentrations between days 2 and 28 postdose. AUC0‐24h and Cmax were dose proportional and showed little accumulation (AUC0_24h ratio between the third and first dose was 1.28). Prolonging the infusion from 5 to 15 minutes lowered Cmax by 34%, with no effect on AUC0‐24h. Urinary excretion of zoledronic acid was independent of infusion duration, dose, or number of doses, showing average Ae0‐24h of 38% ± 13%, 41% ± 14%, and 37% ± 17%, respectively, after 4, 8, and 16 mg. Only trace amounts of drug were detectable in post 24‐hour urines. Renal clearance (Ae0‐24h)/(AUC0‐24h) was on average 69 ± 28, 81 ± 40, and 54 ± 34 ml/min after 4, 8, and 16 mg, respectively, and showed a moderate correlation (r = 0.5; p < 0.001) with creatinine clearance, which was 84 ± 23, 82 ± 25, and 80 ± 40 ml/min for the dose groups at baseline. Adverse events and changes from baseline in vital signs and clinical laboratory variables showed no relationship in terms of type, frequency, or severity with zoledronic acid dose or pharmacokinetic parameters. Zoledronic acid produced significant declines from baseline in serum and/or creatinine‐corrected urine C‐telopeptide (by 74%), N‐telopeptide (69%), pyridinium cross‐links (19–33%), and calcium (62%), with an increasing trend (by 12%) in bone alkaline phosphatase. There was no relationship of the magnitude and duration of these changes with zoledronic acid dose, Ae0‐24j, AUC0‐24h, or Cmax. The antiresorptive effects were evident within 1 day postdose and were maintained over 28 days across all dose levels, supporting monthly dosing with 4 mg zoledronic acid.

The Pharmacokinetics and Pharmacodynamics of Zoledronic Acid in Cancer Patients with Varying Degrees of Renal Function

An open‐label pharmacokinetic and pharmacodynamic study of zoledronic acid (Zometaθ) was performed in 19 cancer patients with bone metastases and known, varying levels of renal function. Patients were stratified according to creatinine clearance (CLcr) into different groups of normal (CLcr > 80 mL/min), mildly (CLcr = 50–80 mL/min), or moderately/severely impaired (CLcr = 10–50 mL/min) renal function. Three intravenous infusions of 4 mg zoledronic acid were administered at 1‐month intervals between doses. Plasma concentrations and amounts excreted in urine were determined in all subjects, and 4 patients were administered 14C‐labeled zoledronic acid to assess excretion and distribution of drug in whole blood. In general, the drug was well tolerated by the patients. Mean area under the plasma concentration versus time curve and mean concentration immediately after cessation of drug infusion were lower, and mean amounts excreted in urine over 24 hours from start of infusion were higher in normal subjects than in those with impaired renal function (36% vs. 28% of excreted dose), although the differences were not significant. Furthermore, with repeated doses, there was no evidence of drug accumulation in plasma or changes in drug exposure in any of the groups, nor was there any evidence of changes in renal function status. Serum levels of markers of bone resorption (serum C‐telopeptide and N‐telopeptide) were noticeably reduced after each dose of zoledronic acid across all three renal groups. It was concluded that in patients with mildly to moderately reduced renal function, dosage adjustment of zoledronic acid is likely not necessary.

Imatinib Disposition and ABCB1 (MDR1, P-Glycoprotein) Genotype

The aim of this study was to explore the impact of individual variation in drug elimination on imatinib disposition. Twenty‐two patients with gastrointestinal stromal tumor or chronic myeloid leukemia initially received imatinib 600 mg daily with dosage subsequently toxicity adjusted. Pharmacokinetic parameters on day 1 and at steady‐state were compared with elimination phenotype and single‐nucleotide polymorphisms of CYP3A5 and ABCB1. A fivefold variation in estimated imatinib clearance (CL/F) was present on day 1 and mean CL/F had fallen by 26% at steady state. This reduction in imatinib CL/F was associated with ABCB1 genotype, being least apparent in thymidine homozygotes at the 1236T>C, 2677G>T/A and 3435C>T loci. Toxicity‐related dose reduction also tended to be less common in these individuals. ABCB1 genotype was associated with steady‐state CL/F due to an apparent genotype‐specific influence of imatinib on elimination. Further evaluation of ABCB1 genotype and imatinib dosage is warranted.

Clinical Pharmacokinetics of the BCR–ABL Tyrosine Kinase Inhibitor Nilotinib

This article describes studies that investigated the pharmacokinetics of nilotinib, a highly specific, oral, second‐generation BCR–ABL tyrosine kinase inhibitor. After a once‐ or twice‐daily regimen at doses ranging from 50 to 1,200 mg/day in 119 patients with chronic myeloid leukemia (CML), the area under the serum concentration–time curve (AUC) and peak serum concentration (Cmax) of nilotinib were found to be nearly dose proportional up to a dose of 400 mg once daily. Solubility‐limited absorption at higher doses was observed, but this was partially overcome by dividing the daily dose into two. For instance, the administration of 400 mg nilotinib twice daily resulted in a 35% increase in AUC as compared to a once‐daily dose of 800 mg. Exploratory pharmacodynamic assessment showed a general trend of greater reduction in white blood cell (WBC) levels with increase in nilotinib concentrations. This finding was consistent with the observation of an 82% reduction in WBC levels in patients after a regimen of 400 mg nilotinib twice daily for 15 days. The type and quantity of food intake variably affected nilotinib absorption. When administered after a high‐fat meal, the AUC of nilotinib increased by 50% in CML patients (n = 10) and by 82% in healthy volunteers (n = 44).

Biodistribution and Plasma Protein Binding of Zoledronic Acid

The bisphosphonate zoledronic acid is a potent inhibitor of osteoclast-mediated bone resorption. To investigate drug biodistribution and elimination, 14C-zoledronic acid was administered intravenously to rats and dogs in single or multiple doses and assessed for its in vitro blood distribution and plasma protein binding in rat, dog, and human. Drug exposure in plasma, bones, and noncalcified tissues was investigated up to 240 days in rats and 96 h in dogs using radiometry after dissection. Drug biodistribution in the rat and within selected bones from dog was assessed by autoradiography. Concentrations of radioactivity showed a rapid decline in plasma and noncalcified tissue but only a slow decline in bone, to ∼50% of peak at 240 days post dose, whereas the terminal half-lives (50–200 days) were similar in bone and noncalcified tissues, suggesting redistribution of drug from the former rather than prolonged retention in the latter. Uptake was highest in cancellous bone and axial skeleton. At 96 h after dose, the fraction of dose excreted was 36% in rat and 60% in dog; 94 to 96% of the excreted radioactivity was found in urine. Blood/plasma concentration ratios were 0.52 to 0.59, and plasma protein binding of zoledronic acid was moderate to low in all species. The results suggest that a fraction of zoledronic acid is reversibly taken up by the skeleton, the elimination of drug is mainly by renal excretion, and the disposition in blood and noncalcified tissue is governed by extensive uptake into and slow release from bone.

OctreoTherTM: Ongoing Early Clinical Development of a Somatostatin-Receptor-Targeted Radionuclide Antineoplastic Therapy

OctreoTherTM (90Y-DOTA-D-Phe1-Tyr3-octreotide, a.k.a. 90Y-SMT 487) consists of a somatostatin peptide analogue (Tyr3-octreotide), coupled with a complexing moiety (DOTA), and labeled with a tightly bound beta-emitter (yttrium-90). By targeting somatostatin receptor-positive tumors (as imaged by OctreaScan®) it may deliver a tumoricidal dose of radiation. Phase I clinical trials, conducted in patients with neuroendocrine tumors, established the safety and tolerability of the dose selected for further study and demonstrated the capacity of OctreoTher to deliver radiation doses to tumors that resulted in significant neuroendocrine tumor shrinkage. Novartis-sponsored phase II studies will soon begin to test the efficacy of OctreoTher in breast and small cell lung cancer. A fixed-dose regimen of 120 mCi/cycle × 3 cycles administered with concomitant amino acid infusion has been chosen for the study. Phase I data and published literature support that this fixed dose regimen will be safely tolerated.

Pharmacokinetic‐pharmacodynamic comparison of a novel multiligand somatostatin analog, SOM230, with octreotide in patients with acromegaly

Acromegaly is a serious hormonal disorder resulting from a pituitary adenoma causing excess growth hormone (GH) production. Somatostatin analogs such as octreotide have been the medical treatment of choice. SOM230, a novel somatostatin analog, was compared with octreotide with respect to pharmacokinetic (PK) profiles and inhibition of GH secretion in acromegalic patients.

Effect of the Proton Pump Inhibitor Esomeprazole on the Oral Absorption and Pharmacokinetics of Nilotinib

Nilotinib (Tasigna), a highly selective and potent BCR‐ABL tyrosine kinase inhibitor (TkI), is administered orally and has pH‐dependent aqueous solubility, with lower dissolution at higher pH. This study evaluated the effect of esomeprazole on the pharmacokinetics of nilotinib in healthy participants. Twenty‐two participants (6 women, 16 men, mean age of 44.9 ± 12.9 years) were enrolled to receive nilotinib as a single oral 400‐mg dose on days 1 and 13 and esomeprazole as 40 mg once daily on days 8 to 13. Serial blood samples were collected up to 72 hours after nilotinib dosing, and nilotinib serum concentrations were determined by a validated liquid chromatography/ tandem mass spectrometry assay. Gastric pH was also monitored in all participants. When coadministered with esomeprazole, nilotinib Cmax was decreased by 27% and AUC0‐∞ decreased by 34%. Nilotinib tmax was prolonged from 4.0 to 6.0 hours, but t1/2 was not altered. Mean gastric pH was 1.0 ± 0.5 at baseline and increased to 2.79 ± 2.50, 3.98 ± 2.27, 5.30 ± 1.70, 5.38 ± 1.26, and 5.31 ± 1.42 at predose and 1, 2, 3, and 4 hours after the fifth esomeprazole dose, respectively. These results suggested a modest reduction in the rate and extent of nilotinib absorption by esomeprazole. Nilotinib is a TKI that may be used concurrently with esomeprazole or other proton pump inhibitors.

Effect of Grapefruit Juice on the Pharmacokinetics of Nilotinib in Healthy Participants

Nilotinib (Tasigna; Novartis Pharmaceuticals) is a second‐generation BCR‐ABL tyrosine kinase inhibitor newly approved for the treatment of imatinib‐resistant or imatinib‐intolerant Philadelphia chromosome positive (Ph+) chronic myeloid leukemia in chronic phase or accelerated phase. This study evaluated the effect of grapefruit juice on the pharmacokinetics of nilotinib in 21 healthy male participants. All participants underwent 2 study periods during which they received a single oral dose of 400 mg nilotinib with 240 mL double‐strength grapefruit juice or 240 mL water in a crossover fashion. Serial blood samples were collected for the determination of serum nilotinib concentrations by a validated liquid chromatography/tandem mass spectrometry assay. Concurrent intake of grapefruit juice increased the nilotinib peak concentration (Cmax) by 60% and the area under the serum concentration‐time curve (AUC>0–∞) by 29% but did not affect the time to reach Cmax or the elimination half‐life of nilotinib. The most common adverse events were headache and vomiting, which were mild or moderate in severity, and their frequency appeared to be similar between 2 treatments. Based on the currently available information about nilotinib and the observed extent of increase in nilotinib exposure, concurrent administration of nilotinib with grapefruit juice is not recommended.