Can severe vincristine neurotoxicity be prevented?

Summary Neurotoxicity in vincristine treatment has generally been considered a consequence of the cumulative dose of the drug, and liver dysfunction has been recognised as an indication to reduce the dosage. We demonstrate that neurotoxicity is also related to individual doses and that even when there is no other evidence of liver dysfunction, a raised level of serum alkaline phosphatase may predict severe neurotoxicity.Exposure to vincristine following IV injection of the drug was studied in 27 subjects by measuring the area under the vincristine plasma concentration time curve (AUC_0–). A statistically significant relationship was found between the AUC_0– and the degree of neurotoxicity. The AUC_0– was related both to dose and to elevation of serum alkaline phosphatase, suggesting that elimination of the drug is impaired when serum alkaline phosphatase is raised. Among patients with elevated serum alkaline phosphatase, a small reduction in the dose of the drug resulted in lower vincristine plasma AUC_0– and less neurotoxicity.     

The pharmacokinetics of vincristine in man:

Summary A radioimmunoassay has been used to investigate the pharmacokinetics of vincristine in 39 cancer patients who received between 0.4 and 1.54 mg vincristine/m² as part of standard treatment protocols. There was wide interindividual variation in both the terminal elimination half-life of vincristine (t_1/2) and the associated volume of distribution (Vd), resulting in an 11-fold range of dose-corrected area under the plasma concentration versus time curve values (AUC_0–). Elevated vincristine AUC_0– values were observed in those patients with raised serum alkaline phosphatase at the time of vincristine estimation. The t_1/2 was significantly longer in these patients than in those with serum alkaline phosphatase within normal limits, suggesting that biochemical evidence of cholestasis is associated with reduced clearance of vincristine. Evidence is also presented to suggest that the clearance of vincristine is dose-dependent within the therapeutic dose range. We observed a disproportionate rise in vincristine plasma concentration at doses exceeding 1 mg/m², due primarily to a lengthening of mean t_1/2 compared with that observed for patients receiving 1 mg vincristine/m² or less.     

Influence of the cardioprotective agent dexrazoxane on doxorubicin pharmacokinetics in the dog

Summary The influence of dexrazoxane on doxorubicin pharmacokinetics was investigated in four dogs using the two treatment sequences of saline/doxorubicin or dexrazoxane/doxorubicin. Intravenous doses of 1.5 mg/kg doxorubicin and 30 mg/kg (the 20-fold multiple) dexrazoxane were given separately, with doxorubicin being injected within 1 min of the dexrazoxane dose. Both doxorubicin and its 13-dihydro metabolite doxorubicinol were quantified in plasma and urine using a validated high-performance liquid chromatographic (HPLC) fluorescence assay. The doxorubicin plasma concentration versus time data were adequately fit by a three-compartment model. The mean half-lives calculated for the fast and slow distributive and terminal elimination phases in the saline/doxorubicin group were 3.0±0.5 and 32.2±12.8 min and 30.0±4.0 h, respectively. The model-predicted plasma concentrations were virtually identical for the saline and dexrazoxane treatment groups. Analysis of variance of the area under the plasma concentration-time curve (AUC_0–), terminal elimination rate (_Z), systemic clearance (CL _s), and renal clearance (CL _r) for the parent drug showed no statistically significant difference (P<0.05) between the two treatments. Furthermore, the doxorubicinol plasma AUC_0– value and the doxorubicinol-to-doxorubicin AUC_0– ratio showed no significant difference, demonstrating that dexrazoxane had no effect on the metabolic capacity for formation of the 13-dihydro metabolite. The total urinary excretion measured as parent drug plus doxorubicinol and the metabolite-to-parent ratio in urine were also unaffected by the presence of dexrazoxane. The myelosuppressive effects of doxorubicin as determined by WBC monitoring revealed no apparent difference between the two treatments. In conclusion, these results show that drug exposure was similar for the two treatment arms. No kinetic interaction with dexrazoxane suggests that its coadministration is unlikely to modify the safety and/or efficacy of doxorubicin.     

Effect of rifampicin on the pharmacokinetics of imatinib mesylate (Gleevec,STI571) in healthy subjects

Objective This study was carried out to investigate the influence of CYP3A induction with rifampicin on imatinib (Gleevec) exposure.Methods The study employed a single center, single-sequence design. A group of 14 healthy male and female subjects received imatinib as a single 400 mg oral dose on two occasions: on study day 1 and on study day 15. Rifampicin treatment (600 mg once daily) for CYP4503A induction was initiated on study day 8 and maintained until day 18. Imatinib pharmacokinetics were determined up to 96 h after dosing on day 1 (no induction) and on days 15–18 (during concomitant rifampicin). Plasma concentrations of imatinib and its main metabolite CGP74588 were determined using a LC/MS/MS method. The ratio of 6-hydroxycortisol to cortisol excreted in the urine was measured to monitor the induction of CYP3A.Results During concomitant rifampicin administration, the mean imatinib C_max, AUC_0–24 and AUC_0– decreased by 54% (90% CI: 48–60%), 68% (64–70%) and 74% (71–76%), respectively. The increase in clearance (Cl/f) was 385% (348–426%) during rifampicin treatment. The mean C_max and AUC_0–24 of the metabolite CGP74588 increased by 88.6% (68.3%–111.4%) and 23.9% (13.5%–35.2%) after rifampicin pretreatment. However, the AUC_0– decreased by 11.7% (3.3–19.4%). All subjects demonstrated a marked induction of hepatic microsomal CYP3A analyzed by the excretion ratio of 6-hydroxycortisol to cortisol from a mean baseline concentration of 5.6 U to 50.5 U.Conclusion Concomitant use of imatinib and rifampicin or other potent inducers of CYP4503A may result in subtherapeutic plasma concentrations of imatinib. In patients in whom rifampicin or other CYP3A inducers are prescribed, alternative therapeutic agents with less potential for enzyme induction should be selected.This work was submitted as an abstract to the 44th Annual Meeting of The American Society of Hematology (ASH), Philadelphia, USA. Abstract published in Blood, vol 100, no. 11, abstract no. 4364, November 2002.A.E.B., B.P., M.H., A.K.-B. and R.C. are employees of Novartis U.K. and M.S. received grant support from Novartis Pharma AG for the conduct of the study.     

Phase I and pharmacokinetic study of KW-2170, a novel pyrazoloacridone compound,in patients with malignant tumors

Purpose The primary purposes of this study were to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD), to recommend a dose for phase II studies, and to analyze the pharmacokinetics of KW-2170. A secondary purpose was to assess tumor response to KW-2170.Experimental design KW-2170 was given as a 30-min i.v. infusion every 4 weeks. Doses were escalated from 1.0 mg/m² according to a modified Fibonacci method.Results A total of 45 cycles of KW-2170 were delivered to 41 patients at doses ranging from 1.0 to 53.0 mg/m². The primary DLT was neutropenia which was observed in two of six patients treated at 32.0 mg/m² and in two of two patients treated at 53.0 mg/m²; therefore, the MTD was 53.0 mg/m². Although no patients showed a complete response (CR) or partial response (PR), 15 patients were evaluated as having freedom from progression at the 1-month time-point, with two demonstrating slight tumor shrinkage in their metastatic lesions. None of the patients experienced significant cardiotoxicity. The plasma concentration of KW-2170 declined in a triphasic manner. The half-life, total clearance (CL_tot) and volume of distribution (V_dss) were nearly constant and independent of dose, and showed a relatively small interpatient variability. A linear relationship was observed between dose and maximum plasma concentration (C_max) and area under the concentration–time curve (AUC_0–). In addition, there was a good correlation between neutropenia and AUC_0–. This suggests that toxicity may be dependent on systemic exposure to the drug. Two oxidative metabolites were observed in the patients plasma and urine.Conclusions The primary DLT of KW-2170 in this study was neutropenia, with a MTD of 53 mg/m². A significant linear relationship was observed between neutropenia and AUC_0–. We estimate the recommended dose for phase II studies to be 41.0 mg/m².     

Pharmacokinetic contribution to the improved therapeutic selectivity of a novel bromoethylamino prodrug (RB 6145) of the mixed-function hypoxic cell sensitizer/cytotoxin α-(1-aziridinomethyl)-2-nitro-1H-imidazole-1-ethanol (RSU 1069)

Summary RB 6145 is a novel hypoxic cell sensitizer and cytotoxin containing both an essential bioreductive nitro group and a bromoethylamino substituent designed to form an alkylating aziridine moiety under physiological conditions. In mice, RB 6145 is 2.5 time less toxic but only slightly less active than the aziridine analogue RSU 1069, giving rise to an improved therapeutic index. However, the mechanism for the enhanced selectivity is not clear. Reasoning that this may lie in a more beneficial pharmacokinetic profile, we investigated the plasma pharmacokinetics, tissue distribution and metabolism of RB 6145 in mice using a specially developed reversed-phase HPLC technique. An i.p. dose of 190 mg kg^–1 (0.5 mmol kg^–1) RB 6145 produced peak plasma concentrations of about 50 g ml^–1 of the pharmacologically active target molecule RSU 1069 as compared with levels of around twice this value that were obtained using an equimolar i.p. dose of RSU 1069 itself. The plasma AUC_0– value for administered RSU 1069 was ca. 47 g ml^–1 h and that for the analogue RSU 1069 was ca. 84 g ml^–1 h. No prodrug was detectable. Another major RB 6145 metabolite in plasma was the corresponding oxazolidinone, apparently formed on interaction of the drug with hydrogen carbonate. The oxazolidinone initially occurred at higher concentrations than did RSU 1069, with the levels becoming very similar from 30 min onwards. Post-peak plasma concentrations of both RB 6145 metabolites declined exponentially, displaying an eliminationt _1/2 of ca. 25 min, very similar to the 30-min value observed for injected RSU 1069. The plasma AUC_0– value for the metabolite RSU 1069 was about 1.3 and 1.6 times higher following i.p. injection of 95 mg kg^–1 (0.25 mmol kg^–1) of the prodrug as compared with administration via the oral and i.v. routes, respectively. After i.v. injection, peak levels of the oxazolidinone metabolite were twice those observed following both i.p. and oral dosing and possibly contributed to the acute toxicity. After an i.p. dose of 190 mg kg^–1 RB 6145, concentrations of RSU 1069 and the oxazolidinone metabolites rose to 40% and 33%, respectively, of the ambient plasma level in i.d. KHT tumours. The peak level of metabolite RSU 1069 was ca. 6 g g^–1 as compared with 10 g g^–1 following an equimolar dose of RSU 1069 itself; the tumour AUC_0– value for the metabolite RSU 1069 was some 35% lower. The AUC_0– in brain for RSU 1069 formed from RB 6145 was about 1.8 times lower than that obtained using an equimolar dose of the analogue RSU 1069. The hydrophilic oxazolidinone metabolite of RB 6145 showed tumour penetration similar to that of the metabolite RSU 1069 but was substantially excluded from brain tissue. About 34% of the delivered dose of RB 6145 appeared in the urine as the oxazolidinone and 12% as RSU 1069. We feel that the improved antitumour specificity observed for RB 6145 as compared with RSU 1069 may be explained at least in part by the more favourable tissue disposition of the metabolites, particularly the similar uptake of both the RSU 1069 metabolite and the oxazolidinone by tumour tissue, coupled with the lower brain exposure following prodrug administration.     

Pharmacokinetic interaction between ketoconazole and imatinib mesylate (Glivec) in healthy subjects

The study under discussion was a drug–drug interaction study in which the effect of ketoconazole, a potent CYP450 3A4 inhibitor, on the pharmacokinetics of Glivec (imatinib) was investigated. A total of 14 healthy subjects (13 male, 1 female) were enrolled in this study. Each subject received a single oral dose of imatinib 200 mg alone, and a single oral dose of imatinib 200 mg coadministered with a single oral dose of ketoconazole 400 mg according to a two-period crossover design. The treatment sequence was randomly allocated. Subtherapeutic imatinib doses and a short exposure were tested in order not to overexpose the healthy volunteers. There was a minimum 7-day washout period between the two sequences. Blood samples for determination of plasma concentrations were taken up to 96 h after dosing. Imatinib and CGP74588 (main metabolite of imatinib) concentrations were measured using LC/MS/MS method and pharmacokinetic parameters were estimated by a non-compartmental analysis. Following ketoconazole coadministration, the mean imatinib C_max, AUC_(0–24) and AUC_(0–) increased significantly by 26% (P<0.005), 40% (P<0.0005) and 40% (P <0.0005), respectively. There was a statistically significant decrease in apparent clearance (CL/f) of imatinib with a mean reduction of 28.6% (P<0.0005). The mean C_max and AUC_(0–24) of the metabolite CGP74588 decreased significantly by 22.6% (P<0.005) and 13% (P<0.05) after ketoconazole treatment, although the AUC_(0–) of CGP74588 only decreased by 5% (P=0.28). Coadministration of ketoconazole and imatinib caused a 40% increase in exposure to imatinib in healthy volunteers. Given its previously demonstrated safety profile, this increased exposure to imatinib is likely to be clinically significant only at high doses. This interaction should be considered when administering inhibitors of the CYP3A family in combination with imatinib.     

The in vivo cytotoxic activity of procarbazine and procarbazine metabolites against L1210 ascites leukemia cells in CDF1 mice and the effects of pretreatment with procarbazine,phenobarbital, diphenylhydantoin,and methylprednisolone upon in vivo procarbazine activity

Summary An in vivo assay of the activity of procarbazine, N-isopropyl--(2-methylhydrazino)-p-toluamide hydrochloride, and several metabolic intermediates against IP-implanted L1210 leukemia cells in CDF₁ male mice is described. Treatment of tumor-bearing mice with procarbazine at doses of 300–500 mg/kg IP increased the mean lifespan of treated mice by 29%–32% relative to that of untreated animals. Procarbazine treatment with doses of 200–400 mg/kg/day given IP for 3 consecutive days increased mean lifespan by 39%–46%. The major circulating metabolite, azoprocarbazine (N-isopropyl--(2-methylazo)-p-toluamide), was as active as procarbazine when administered at equivalent doses for 3 consecutive days. A 2:1 mixture of azoxyprocarbazines (N-isopropyl--(2-methyl-ONN-azoxy)-: and N-isopropyl--(2-methyl-NNO-azoxy)-p-toluamide) was more active than procarbazine, increasing mean lifespan by 76% using the 3-consecutive-day dose schedule.The effects of pretreatment with procarbazine and drugs that are often co-administered with procarbazine, i.e., phenobarbital, diphenylhydantoin, and methylprednisolone, upon procarbazine anticancer activity against L1210 ascites leukemia cells was also determined. Pretreatment of CDF₁ male mice with phenobarbital and diphenylhydantoin for 7 days was found to increase the antineoplastic activity of procarbazine by 13%–24%. Pretreatment with methylprednisolone did not significantly alter procarbazine activity. The effects of pretreatment with procarbazine, which is often administered daily for a period of 2–4 weeks, on procarbazine antineoplastic activity were varied. The results of these preliminary pretreatment studies combined with the finding that procarbazine metabolites have antitumor activity that is equal to or greater than that of the parent drug suggest that current clinical protocols that use procarbazine along with agents capable of altering procarbazine metabolism may involve drug interactions that alter the efficacy of procarbazine as an anticancer agent.     

Pharmacokinetics of etoposide in cancer patients treated with high-dose etoposide and with dexrazoxane (ICRF-187) as a rescue agent

Purpose The pharmacokinetics of etoposide were studied in cancer patients with brain metastases treated with high-dose etoposide in order to determine if the pharmacokinetics were altered by the use of dexrazoxane as a rescue agent to reduce the extracerebral toxicity of etoposide.Methods Etoposide plasma levels were determined by HPLC.Results The etoposide pharmacokinetics described by a monophasic first-order elimination model were found to be similar to other reported data in other settings and at similar doses.Conclusions The pharmacokinetics of etoposide were unaffected by dexrazoxane rescue.Abbreviations AUC_0– Area under the curve from time zero to infinity - C_max Maximum plasma concentration of drug - Cl_tot Total plasma clearance - HPLC High-pressure liquid chromatography - P_oct Octanol-water partition coefficient - t_1/2 Beta phase plasma elimination half-time - t_r Retention time Patricia Schroeder and Kenneth Hofland contributed equally to this work.     

Daunorubicin and daunorubicinol pharmacokinetics in plasma and tissues in the rat

Recent evidence suggests that 13-hydroxy metabolites of anthracyclines may contribute to cardiotoxicity. This study was designed to determine the pharmacokinetics of daunorubicin and the 13-hydroxy metabolite daunorubicinol in plasma and tissues, including the heart. Fisher 344 rats received 5 mg kg^–1 daunorubicin i.v. by bolus injection. Rats were killed at selected intervals for up to 1 week after daunorubicin administration for determination of concentrations of daunorubicin and daunorubicinol in the plasma, heart, liver, kidney, lung, and skeletal muscle. Peak concentrations of daunorubicin were higher than those of daunorubicinol in the plasma (133±7 versus 36±2 ng ml^–1;P<0.05), heart (15.2±1.4 versus 3.4±0.4 g g^–1;P<0.05), and other tissues. However, the apparent elimination half-life of daunorubicinol was longer than that of daunorubicin in most tissues, including the plasma (23.1 versus 14.5 h) and heart (38.5 versus 19.3 h). In addition, areas under the concentration/time curves (AUC) obtained for daunorubicinol exceeded those found for daunorubicin in almost all tissues, with the ratios being 1.9 in plasma and 1.7 in the heart. The ratio of daunorubicinol to daunorubicin concentrations increased dramatically with time from <1 at up to 1 h to 87 at 168 h in cardiac tissue. Thus, following daunorubicin injection, cumulative exposure (AUC) to daunorubicinol was greater than that to daunorubicin in the plasma and heart. If daunorubicinol has equivalent or greater potency than daunorubicin in causing impairment of myocardial function, it may make an important contribution to the pathogenesis of cardiotoxicity.     

Pharmacological disposition of 1,4-dihydroxy-5-8-bis[[2[(2-hydroxyethal)amino] ethyl]amino]-9,10-anthracenedione dihydrochloride in the dog

Summary DHAQ, a new antitumor agent, has been selected for clinical trial on the basis of its activity against a number of transplantable rodent tumors. In anticipation of the clinical trial of this agent, the pharmacology of DHAQ was studied in beagles by high-pressure liquid chromatographic and radiochemical techniques that are specific for the unchanged drug. ¹⁴C-DHAQ was administred IV to beagles at a dose of 5 mg/kg, 100–125 Ci total. With a maximal plasma concentration of 75 = 2.7 ng/ml, DHAQ was eliminated from the plasma with a half-life of 28.1 h during the terminal phase. The total clearance of DHAQ was 10.1±0.4 mg/kg/min, while the apparent volume of distribution was 26.6±4.9 l/kg. In 48 h 2.4%±0.6% of the dose was excreted in the urine and 3.0%±0.1% in the bile as the unchanged drug. At autopsy performed 5 h after dosing, the highest percentage of the administered DHAQ was in the liver (49.7%±2.7%), followed by the small intestine (7.1%±0.7%), kidneys (2.7%±0.1%), lung (1.9%±0.3%), spleen (1.6%±0.3%), and stomach (1.3%±0.1%). The heart, large intestine, pancreas, gallbladder, urinary bladder, and brain each retained less than 1% of the dose. However, 24 h after dosing 10.6% of the drug was detected in the liver and 2.9% in the small intestine. In terms of the percentage of the dose, the distribution of DHAQ in the other organs either remained unchanged or increased slightly. In concentrations varying from 10 ng/ml to 10 g/ml the drug was 70%–80% bound to plasma protein. DHAQ was metabolized to two unidentified metabolites. Thus, this drug appeared to be cleared from the plasma of beagle dogs chiefly by tissue binding, leading to possible persistence of the drug in certain body compartments.     

Bioavailability and pharmacokinetics of the cardioprotecting flavonoid 7-monohydroxyethylrutoside in mice

Purpose The pharmacokinetics and bioavailability of monoHER, a promising protector against doxorubicin-induced cardiotoxicity, were determined after different routes of administration.Methods Mice were treated with 500 mg.kg^–1 monoHER intraperitoneally (i.p.), subcutaneously (s.c.) or intravenously (i.v.) or with 1000 mg.kg^–1 orally. Heart tissue and plasma were collected 24 h after administration. In addition liver and kidney tissues were collected after s.c. administration. The levels of monoHER were measured by HPLC with electrochemical detection.Results After i.v. administration the AUC_{0–120 min} values of monoHER in plasma and heart tissue were 20.5±5.3 mol.min.ml^–1 and 4.9±1.3 mol.min.g^–1 wet tissue, respectively. After i.p. administration, a mean peak plasma concentration of about 130 M monoHER was maintained from 5 to 15 min after administration. The AUC_{0–120 min} values of monoHER were 6.1±1.1 mol.min.ml^–1 and 1.6±0.4 mol.min.g^–1 wet tissue in plasma and heart tissue, respectively. After s.c. administration, monoHER levels in plasma reached a maximum (about 230 M) between 10 and 20 min after administration. The AUC_{0–120 min} values of monoHER in plasma, heart, liver and kidney tissues were 8.0±0.6 mol.min.ml^–1, 2.0±0.1, 22.4±2.0 and 20.5±5.7 mol.min.g^–1, respectively. The i.p. and s.c. bioavailabilities were about 30% and 40%, respectively. After oral administration, monoHER could not be detected in plasma, indicating that monoHER had a very poor oral bioavailability.Conclusions MonoHER was amply taken up by the drug elimination organs liver and kidney and less by the target organ heart. Under cardioprotective conditions (500 mg/kg, i.p.), the C_max was 131 M and the AUC was 6.3 M.min. These values will be considered endpoints for the clinical phase I study of monoHER.     

Oral bioavailability of docetaxel in combination with OC144-093 (ONT-093)

Objective Docetaxel given orally as monotherapy results in low bioavailability of <10%. Previous studies have indicated that the intestinal efflux pump P-glycoprotein (P-gp) prevents uptake from the gut resulting in low systemic exposure to docetaxel. The purpose of this study was to determine the degree of enhancement of the oral uptake of docetaxel on combination with orally administered OC144-093, a potent P-gp inhibitor. Furthermore, the safety of combined treatment was determined and whether known functional genetic polymorphisms of the MDR1 gene could be associated with variability in docetaxel pharmacokinetics was also investigated.Patients and methods A proof of concept study was carried out in 12 patients with advanced solid tumors. Patients were randomized to receive one course of 100 mg oral docetaxel combined with 500 mg OC144-093 followed 2 weeks later by a second i.v. course of docetaxel at a flat dose of 100 mg, without OC144-093, or vice versa. This was followed by standard i.v. docetaxel treatment if indicated.Results The apparent relative oral bioavailability of docetaxel was 26±8%. Orally administered docetaxel combined with oral OC144-093 resulted in a C_max of 415±255 ng ml^–1, an AUC_0– of 844±753 ng h ml^–1 and k_el of 0.810±0.296 h^–1. These values differed significantly from those following i.v. administration of docetaxel, with a C_max of 2124±1054 ng ml^–1, an AUC_0– of 2571±1598 ng h ml^–1 and a k_el of 1.318±0.785 h^–1 (P=0.003, P=0.006, P=0.016). The study medication was well tolerated and most of the adverse events possibly or probably related to OC144-093 and docetaxel were of CTC grade 1 and 2. One patient had a homozygous 3435T/T mutation, which is associated with low intestinal P-gp expression, and two other patients had a homozygous mutation on exon 21.Conclusion The relative apparent bioavailability of 26% was most likely caused by a significant effect of OC144-093 on the oral uptake of docetaxel. Large intrapatient and interpatient (pharmacokinetic) variation was found after oral as well as after i.v. administration of docetaxel. Higher plasma levels were observed after 100 mg i.v. docetaxel than after 100 mg oral docetaxel plus 500 mg oral OC144-093. The safety of the oral combination was good. More patients should be evaluated to determine the effect of P-gp single nucleotide polymorphisms on oral pharmacokinetic values of docetaxel.     

Pharmacokinetics and toxicity of the antitumour agentN-[2-(dimethylamino)ethyl]acridine-4-carboxamide after i.v. administration in the mouse

Summary The pharmacokinetics, tissue distribution and toxicity of the antitumour agentN-[2-(dimethylamino)ethyl]acridine-4-carboxamide(AC) were studied after i.v. administration to mice. Over the dose range of 9–121 mol/kg (3–40 mg/kg), AC displayed linear kinetics with the following model-independent parameters: clearance (C), 21.0±1.9 l h^–1 kg^–1; steady-state volume of distribution (V_ss), 11.8±1.4 l/kg; and mean residence time (MRT), 0.56±0.02 h. The plasma concentration-time profiles for AC fitted a two-compartment model with the following parameters:C _c, 19.4±2.3 l h^–1 kg^–1; V_c, 7.08±1.06 l/kg;t _1/2 13.1±3.5 min; andt _1/2Z, 1.60±0.65 h. AC displayed moderately high binding in healthy mouse plasma, giving a free fraction of 15.9%–25.3% over the drug concentration range of 1–561 M. After the i.v. administration of 30 mol/kg [³H]-AC, high radioactivity concentrations were observed in all tissues (especially the brain and kidney), showing a hight _1/2c value (37–59 h). At 2 min (first blood collection), the AC concentration as measured by high-performance liquid chromatography (HPLC) comprised 61% of the plasma radioactivity concentration (expressed as AC equivalents/l). By 48 h, 73% of the dose had been eliminated, with 26% and 47% of the delivered drug being excreted by the urinary and faecal routes, respectively; <1% of the total dose was excreted as unchanged AC in the urine. At least five distinct radiochemical peaks were distinguishable by HPLC analysis of plasma extracts, with some similar peaks appearing in urine. The 121-mol/kg dose was well tolerated by mice, with sedation being the only obvious side effect and no significant alterations in blood biochemistry or haematological parameters being recorded. After receiving a dose of 152 mol/kg, all mice experienced clonic seizures for 2 min (with one death occuring) followed by a period of sedation that lasted for up to 2h. No leucopenia occurred, but some mild anaemia was noted. There was no significant change in blood biochemistry. A further 20% increase in the i.v. dose (to 182 mol/kg) resulted in mortality, with death occurring within 2 min of AC administration.Supported by the Auckland Medical Research Foundation and the Cancer Society of New Zealand     

The effects of degree of hepatic or renal impairment on the pharmacokinetics of exemestane in postmenopausal women

Purpose Two studies were conducted to compare the pharmacokinetics and tolerability of exemestane in postmenopausal subjects with various degrees of impairment of hepatic or renal function with those in healthy postmenopausal subjects.Methods All subjects were postmenopausal females. In study 1, nine subjects had normal hepatic function (Child-Pugh grade A), and nine had moderately (grade B) and eight severely (grade C) impaired hepatic function. In study 2, six subjects had normal renal function, and six moderately (creatinine clearance, CrCL, 30–60 ml/min per 1.73 m²) and seven severely (CrCL <29 ml/min per 1.73 m²) impaired renal function. Each subject took a single oral dose of 25 mg exemestane. Samples of plasma (to 168 h after dosing) and urine (to 72 h in study 1, or 96 h in study 2) were taken for pharmacokinetic analysis. Safety and tolerability were assessed by monitoring vital signs, laboratory safety tests, ECG and adverse events.Results Exposure to exemestane was increased two- to threefold in patients with hepatic impairment. Thus, the geometric mean AUC_0– values were 41.71 (90% CI 32.2 to 54.0), 99.02 (76.5 to 128.2) and 118.59 ng·h/ml (90.2 to 156.0) in healthy subjects, and in patients with moderate and severe hepatic impairment, respectively (P<0.01). C_max also increased twofold. Compared with healthy subjects, patients with hepatic impairment had lower apparent oral clearance and apparent volume of distribution of exemestane. Renal impairment was also associated with two- to threefold increases in AUC_0–: 34.64 (90% CI 23.9 to 50.2), 94.10 (64.9 to 136.4) and 65.52 ng·h/ml (46.5 to 92.4) in healthy subjects, and in patients with moderate and severe hepatic impairment, respectively (P<0.05). C_max did not change significantly. Apparent oral clearance was directly correlated with CrCL (r²=0.43). Exemestane was tolerated well, with no safety concerns.Conclusions Oral clearance of exemestane was reduced in the presence of significant hepatic or renal disease. However, in view of the relatively large safety margin and the mild nature of the side effects of exemestane, the therapeutic implications of these changes in pharmacokinetics are considered minor and of no clinical significance.     

Bioavailability and pharmacokinetics of the investigational anticancer agent XK469 (NSC 698215) in rats following oral and intravenous administration

Purpose To determine the oral bioavailability of R-XK469, a water-soluble investigational anticancer agent undergoing phase I clinical trials as an intravenous product.Methods R-XK469 was administered to two groups of catheterized Sprague-Dawley rats via the oral and IV routes at a dose of 10 mg/kg and blood samples were collected at predetermined times. XK469 in plasma samples was quantified using a HPLC method. The pharmacokinetic parameters were computed using WinNonlin 4.0.1 software.Results The pharmacokinetic parameters of XK469 following oral and IV administrations, respectively, were (mean±SD): C_max 138±64 and 404±355 g/ml; AUC_0– 2381±773 and 2854±1924 g h/ml; and elimination half-life (T_1/2) 12.9±5.8 and 13.5±7.8 h T_max was 2.92±1.92 h following oral dosing. Oral R-XK469 was 83% bioavailable.Conclusion Together with the antitumor efficacy of oral XK469 shown in preclinical models and its schedule dependency, these results indicate the promise of developing an oral dosage form of R-XK469 for clinical development.     

The disposition of carboplatin in ovarian cancer patients

Summary Carboplatin was given as a 30-min infusion to 11 ovarian cancer patients at doses of 170–500 mg/m². The ages, weights, and creatinine clearances (Cl_cr) ranged from 44 to 75 years, from 44 to 74 kg, and from 32 to 101 ml/min, respectively. Plasma, plasma ultrafiltrate (PU), and urine samples were obtained at appropriate times for 96 h and were analyzed for platinum. The PU and urine were also analyzed for the parent compound by HPLC. In patients with a Cl_cr of about 60 ml/min or greater, carboplatin decayed biexponentially with a mean t_1/2 of 1.6 h and a t_1/2 of 3.0 h. The mean (±SD) residence time, total body clearance, and apparent volume of distribution were 3.5±0.4 h, 4.4±0.85 l/h, and 16±31l, respectively. C_max and AUC_inf values increased linearly with dose, and the latter values correlated better with the dose in mg than in mg/m². No significant quantities of free, ultrafilterable, platinum-containing species other than the parent compound were found in plasma, but platinum from carboplatin became protein-bound and was slowly eliminated with a minimal t_1/2 of 5 days. The major route of elimination was excretion via the kidneys. Patients with a Cl_cr of 60 ml/min or greater excreted 70% of the dose as the parent compound in the urine, with most of this occurring within 12–16 h. All of the platinum in 24-h urine was carboplatin, and only 2%–3% of the dosed platinum was excreted from 48 to 96 h. Patients with a Cl_cr of less than about 60 ml/min exhibited dose-disproportional increases in AUC_inf and MRT values. The latter were inversely related to Cl_cr (r=-0.98). Over a dose range of 300–500 mg/m², carboplatin exhibited linear, dose-independent pharmaco-kinetics in patients with a Cl_cr of about 60 ml/min or greater, but dose reductions are necessary for patients with mild renal failure.Supported in part by CA 16087, CRC-RR-96, AIFCR     

Evaluation of plasma 5-fluorouracil nucleoside levels in patients with metastatic breast cancer: relationships with toxicities

This paper describes the relationship between 5-fluorouracil (FUra)-derived toxicities and plasma levels of the FUra anabolites 5-fluorouridine (FUrd) and 5-fluoro-2-deoxyuridine (FdUrd) monitored in patients receiving continuous infusions of FUra (1000 mg/m² per 24 h) over 5 days preceded by the administration of cisplatin (100 mg/m²). A total of 63 courses of this treatment were given as second-line chemotherapy to 17 patients with metastatic breast cancer. The active FUra anabolites FUrd and FdUrd were monitored twice daily in the plasma by highperformance liquid chromatography. Data were analyzed using multiple analysis of variance (ANOVA). Only a low proportion of patients exhibited measurable plasmatic levels of FUrd (43%) and FdUrd (70%). The areas under the plasma concentration-time curves (AUC) determined over 120 h for FUrd (AUC_FUrd) and for FdUrd (AUC_FdUrd) were found to be statistically significantly different for chemotherapy cycles with and those without myelosuppression. Chemotherapy cycles without neutropenia were associated with low AUC_FUrd values (mean±SEM, 2.9±0.7 g ml^–1 h) and high AUC_FdUrd values (14.1±2.7 g ml^–1 h), respectively, whereas courses with myelosuppression (WHO grades 2–4) showed inverse profiles with high AUC_FUrd values (16.3±2.3 g ml^–1 h) and low AUC_FdUrd values (3.1±1.0 g ml^–1 h), respectively. A statistically significant difference in AUC_FdUrd values was also observed between cycles with and those without mucositis (P=0.0027), with AUC_FdUrd values being 22.6±5.6 and 7.8±1.9 g ml^–1 h, respectively. Whereas hematotoxicity could be correlated with both AUC_FUrd and AUC_FdUrd values, mucositis was associated with high AUC_FdUrd levels. Moreover, a negative correlation was found between the AUCs determined for FUrd and FdUrd (P=0.002), indicating that activation of FUra via FUrd or via FdUrd may involve competitive processes. Therefore, to follow the development of the major FUra-derived toxicities, measurement of FUrd and FdUrd plasma levels appeared very attractive.     

Penetration of etoposide into human malignant brain tumors after intravenous and oral administration

Summary Penetration of etoposide into the cerebrospinal fluid, brain tumor, and brain tissue after intravenous administration was investigated in patients presenting with malignant brain tumors. A relatively low dose (55–65 mg/m²) was used to compare intravenous with oral administration. High-performance liquid chromatography with fluorescence detection was used to evaluate drug levels. Plasma and cerebrospinal fluid levels of etoposide after oral administration (50–150 mg/day) were also studied so as to determine the adequate oral dose for the treatment of malignant brain tumors. The peak plasma concentration after intravenous administration ranged from 7.01 to 10.47 g/ml, varying in proportion to the injected dose, whereas that after oral administration was lower, namely, 1.44–4.99 g/ml, and was unstable when the oral dose was 150 mg daily. The peak cerebrospinal fluid level following either intravenous or oral administration was much lower than the plasma concentration and was influenced by the peak plasma level and the sampling site. The etoposide concentration in cerebrospinal fluid taken from the subarachnoid space and ventricle of patients displaying no tumor invasion and of those presenting with meningeal carcinomatosis and in cerebrospinal fluid taken from the dead space after tumor resection was 0.7%±0.5%, 3.4%±1.0%, and 7.2% ± 8.5%, respectively, of the plasma concentration. Serial oral administration did not result in the accumulation of etoposide in cerebrospinal fluid. The tumor concentration (1.04–4.80 g/g) was 14.0%±2.9% of the plasma level after intravenous administration, was related to the injected dose, and was approximately twice the concentration detected in the brain tissue. Therefore, a relatively low dose of etoposide injected intravenously penetrates the brain tumor at an efficacious concentration. Our results indicate than an oral dose of 100 mg etoposide be given for malignant brain tumors, as limited penetration of the drug into the intracranial region was observed.     

Doxorubicin and doxorubicinol pharmacokinetics and tissue concentrations following bolus injection and continuous infusion of doxorubicin in the rabbit

Cumulative dose-related, chronic cardiotoxicity is a serious clinical complication of anthracycline therapy. Clinical and animal studies have demonstrated that continuous infusion, compared to bolus injection of doxorubicin, decreases the risk of cardiotoxicity. Continuous infusion of doxorubicin may result in decreased cardiac tissue concentrations of anthracyclines, including the primary metabolite doxorubicinol, which may also be an important contributor to cardiotoxicity. In this study, doxorubicin and doxorubicinol plasma pharmacokinetics and tissue concentrations were compared in New Zealand white rabbits following intravenous administration of doxorubicin (5 mg·kg^–1) by bolus and continuous infusion. Blood samples were obtained over a 72-h period after doxorubicin administration to determine plasma doxorubicin and doxorubicinol concentrations. Rabbits were killed 7 days after the completion of doxorubicin administration and tissue concentrations of doxorubicin and doxorubicinol in heart, kidney, liver, and skeletal muscle were measured. In further experiments, rabbits were killed 1 h after bolus injection of doxorubicin and at the completion of a 24-h doxorubicin infusion (anticipated times of maximum heart anthracycline concentrations) to compare cardiac concentrations of doxorubicin and doxorubicinol following both methods of administration. Peak plasma concentrations of doxorubicin (1739±265 vs 100±10 ng·ml^–1) and doxorubicinol (78±3 vs 16±3 ng·ml^–1) were significantly higher following bolus than infusion dosing. In addition, elimination half-life of doxorubicinol was increased following infusion. However, other plasma pharmacokinetic parameters for doxorubicin and doxorubicinol, including AUC, were similar following both methods of doxorubicin administration. Peak left ventricular tissue concentrations of doxorubicin (16.92±0.9 vs 3.59±0.72 g·g^–1 tissue;P<0.001) and doxorubicinol (0.24±0.02 vs 0.09±0.01 g·g^–1 tissue;P<0.01) following bolus injection of doxorubicin were significantly higher than those following infusion administration. Tissue concentrations of parent drug and metabolite in bolus and infusion groups were similar 7 days after dosing. The results suggest that cardioprotection following doxorubicin infusion may be related to attenuation of the peak plasma or cardiac concentrations of doxorubicin and/or doxorubicinol.