Katherine Lu

Pharmacology of mitoxantrone in cancer patients

SummaryRadioactive mitoxantrone was administered at doses of 1–12 mg/m2 by rapid IV infusion to 11 patients. Of the 11 patients, six had normal liver and kidney function tests while the remaining five had abnormal third space and/or hepatic dysfunction. In the former group, the initial t1/2 was 13.7 min and terminal t1/2 was 37.4 h. The apparent volume of distribution was 13.8 l/kg. The total clearance rate was 230.7 ml/kg/h. The recovery of unchanged mitoxantrone from urine was 6.8% at 24 h and 7.3% at 72 h, while the corresponding recovery of total radioactivity was 9.4% at 24 h and 11.3% at 72 h. In the five patients with abnormal liver function or third space the initial t1/2 was variable and ranged from 11.5–63.6 min, and the terminal t1/2 ranged from 53.3–173.2 h, whereas the total clearance rate varied from 52.7–170.2 ml/kg/h. However, the cumulative urinary excretion of unchanged mitoxantrone was similar to that of patients with normal hepatic function: 3.9 at 24 h and 5 at 72 h. Biliary excretion was studied in one of these patients, who had jaundice and hepatic impairment; only 2.3% of 14C was excreted in 24 h and 2.7% in 96 h, of which 39% and 41%, respectively, were unchanged mitoxantrone. Our results suggest that mitoxantrone is taken up rapidly by tissue from which it is released slowly. Reduction of mitoxantrone dose is therefore advisable in patients with liver dysfunction or abnormal third space.

Concentrations of vinblastine in human intracerebral tumor and other tissues

SummaryUptake of vinblastine into human cerebrospinal fluid, intracerebral tumor and autopsy tissues was quantitated radiochemically after separating vinblastine from its metabolites by high pressure liquid chromatography. Only low concentrations of vinblastine were found in cerebrospinal fluid from a single patient. A second patient who received a tracer dose of radiolabelled vinblastine prior to surgical resection of an intracerebral tumor had slightly less radioactivity in tumor than in temporalis muscle, but more in tumor than in edematous brain surrounding the tumor. The radioactivity in tumor increased gradually and exceeded concurrent plasma radioactivity by 2 hr after drug administration. A third patient died 4 hr into a planned 24-hr infusion of radiolabeled vinblastine. Highest vinblastine concentrations were found in organs with high blood flow such as kidney and heart. Intermediate concentrations were found in liver and lung, and low concentrations were found in prostate, gastrointestinal tract, spleen, muscle, bladder, and hepatic and lymph node metastases. A fourth patient died one month after receiving radiolabeled vinblastine. Highest concentrations were in liver and next highest concentrations were in intracerebral tumor. Moderately high concentrations were found in pancreas, thyroid, lung, spleen, ovary, kidney, and kidney metastases. Lowest concentrations were found in omental metastases, heart, breast, and brain. Vinblastine concentration decreased with increasing distance into brain from the brain metastases. Thus, vinblastine was not selectively localized in tumors. The concentrations in tumor did not reflect the concentration in the organ in which the tumor was located. There was no indication that uptake into intracerebral tumor was impaired. Cerebrospinal fluid and brain concentrations of vinblastine did not give any indication of the concentration attainable in intracerebral tumor.

Clinical pharmacology of 4-demethoxydaunorubicin (DMDR)

SummaryDMDR, a daunorubicin derivative with a higher therapeutic index and lower cardiotoxicity than either the parent drug or doxorubicin, is active when given PO in experimental animals. We studied its pharmacokinetics in ten patients receiving DMDR IV or PO or IV and PO sequentially at 10–12.5 mg/m2. DMDR and its metabolites were quantified by high-performance liquid chromatography and fluorometry. In nine patients who received DMDR IV the unchanged drug disappeared from the plasma biphasically with a mean terminal half-life of 27.0±5.5 h, an apparent volume of distribution of 63.9±12.61 kg-1, and a total clearance of 1.9±0.41 kg-1 h-1. In 24 h only 5.1%±1.1% of the dose was excreted in the urine. In comparison, in 19 studies the plasma half-life of DMDR given PO was 34.8±6.7 h, 2.3%±1.3% was excreted in the urine in 24 h, and the maximum plasma drug concentration was reached in about 1 h. The bioavailability of DMDR given PO was about 39% according to comparison of the areas under the plasma DMDR concentration versus time curves for the two routes, but 45% according to comparison of the 24-h cumulative urinary excretion rates. In one patient with severe liver dysfunction following oral administration, the plasma DMDR half-life was 56.8 h, more than twice the average length. By either route, the drug was quickly metabolized to one major metabolite, DMDR-ol. The plasma half-life of DMDR-ol was 72.5±24.7 h, or 35.7±7.4 when DMDR was administered IV or PO. In the plasma, DMDR-ol always exceeded DMDR in concentration. Moreover, the 24 h cumulative urinary excretion of DMDR-ol as a percentage of the dose of DMDR administered was 7.8 following IV and 7.4 following PO administration.

Intracerebral penetration and tissue distribution of 2,5-diaziridinyl 3,6-bis(carboethoxyamino) 1,4-benzoquinone (AZQ, NSC-182986)

Abstract[14C]AZQ (2–4 mg/m2, 100–200 mCi) was administered at varying times to five patients undergoing surgical resection of intracerebral tumors. Plasma, cerebrospinal fluid (CSF), edematous brain, and tumor specimens were obtained during surgery and the concentration of AZQ was determined radiochemically and chromatographically. Total [14C]AZQ equivalent concentration in tumor for two patients was determined to be 47.5% and 85% of concurrent plasma concentration which was similar to that found in normal brain (60.4% and 75.5% respectively). Only 18–45% of the total radioactivity in tumor tissue and 30–56% in plasma were accounted for by unchanged AZQ. These findings suggest that AZQ may be metabolized to a certain extent. Tissue samples from various organs were obtained during autopsy in a patient who expired ten days after AZQ administration. The highest AZQ concentration was found in the liver, followed by the kidney. Comparable amounts were found in normal brain and brain tumor (22 ng/ g vs. 31 ng/ g respectively). These results indicate that AZQ penetrates readily into the normal brain and brain tumor with a tendency to persist.

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

SummaryDHAQ, 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 μCi 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 μg/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.

Clinical kinetics of 1,4-dihydroxy-5,8-bis [[2- [(2-hydroxyethyl)amino]ethyl] amino]-9,10-anthracenedione

The clinical kinetics of 1,4‐dihydroxy‐5,8‐bis[[2‐[(2‐hydroxyethyl)amino]ethyl]amino]‐9,10‐anthracenedione dihydrochloride (DHAQ) are reported. DHAQ, 1 to 3 mg/m2, was administered as an intravenous bolus to six patients with metastatic cancer. Plasma clearance of the drug followed a biphasic pattern with a harmonic mean initial half‐life (t½) of 13.7 min and a terminal t½ of 37.4 hr. Recovery of unchanged drug in the urine was 6.8% at 24 hr and 7.3% at 72 hr, while the corresponding recovery of total radioactivity was 9.4% and 11.3%. Apparent volume of distribution of DHAQ was about 13.8 ±2.9 l/kg. Total clearance was 238.7 ml/kg/hr, twice the creatinine clearance.

Central nervous system (CNS) penetration of homoharringtonine (HHT)

Generally tritiated homoharringtonine ([3H]HHT, 150 μCi, 430 μg) was administered intravenously to seven patients at varying times before surgical resection of malignant brain tumor. Plasma, urine, cerebrospinal fluid (CSF), and tumor specimens were obtained during surgery, and the concentrations of HHT, its major metabolite, and [3H]HHT equivalent were determined chromatographically and radiochemically. For [3H]HHT equivalent, the concentration in tumor ranged from 0.6 to 4.3 ng/g and the ratio of tumor to plasma concentration from 0.5 to 1.8. In one patient who had CSF available for drug determination, the CSF to plasma ratio of total [3H]HHT was 0.3 at 45 minutes after drug administration and less than 0.2 ng/ml was unchanged HHT. For unchanged HHT, drug concentration in tumor ranged from undetectable (4 patients) to 1.8 ng/g. A major metabolite of HHT was detectable in the tumor specimens of all the patients. These results indicate that homoharringtonine can penetrate into brain tumors; in 3 patients with brain tumors, the ratios of HHT concentration in the tumor to that in the concurrent plasma were greater than one.

Clinical pharmacological and toxicological studies of Cis-diamminedichloroplatinum (II) by continuous intravenous infusion

Summary Pharmacological and toxicological studies of DDP were conducted in 35 patients with solid tumors, who received a priming dose of the agent at 5 mg/m 2 followed by continuous i.v. infusion at 20 mg/m 2 daily for 5 days. DDP in biological fluids was determined either colorimetrically or by atomic absorption spectrometry. Upon cessation of infusion, the average terminal plasma t½ of DDP in 7 patients was 34.7 hr; however, in a patient with oliguric renal failure, it was 96 hr. During infusion, plasma DDP concentrations varied between 0.5–4.3 mg/l. The cumulative urinary excretion of DDP was 34 per cent in 8 days. In concentrations of 1–50 mg/l DDP was 26–56 per cent bound to human plasma protein at 28°. The toxicity of DDP by i.v. infusion included nausea and vomiting in 94 per cent of the patients, but of much less severity than by other schedules. Additionally, nephrotoxicity was seen in 21 per cent of the patients, and tinnitus or audiogram abnormalities in 10 per cent; hematologic toxicity was mild. Complete remission lasting more than 4 months was seen in a patient with basal cell carcinoma. Also, of 7 patients with squamous cell carcinoma of the head and neck or cervix, 3 showed partial remission and 2 showed stabilization of their disease. Continuous i.v. infusion therefore offers the advantage of attenuating the nausea and vomiting caused by DDP.

Phase I clinical trial and pharmacokinetic evaluation of 4′-0-tetrahydropyranyladriamycin (THP-adriamycin)

SummaryTetrahydropyranyladriamycin (THP-adriamycin) is an anthracycline analogue currently under development in Europe and Japan. Preclinical studies suggest that it may have greater activity and less cardiac toxicity than doxorubicin. We conducted a phase I clinical and pharmacologic study of THP-adriamycin given as a weekly 15-min infusion for 3 weeks, followed by 1 week of observation. Therapy was associated with minimal acute toxicity. The dose-limiting toxicity was neutropenia, usually maximal during the 4th week after treatment; alopecia was rare. The maximum tolerated dose was 25 mg/m2; for phase II studies using this schedule, a dose of 20 mg/m2 weekly for 3 weeks is recommended. Pharmacokinetic studies revealed a triphasic elimination of the parent compound with α, β, and γ half-lives of 5.6 min, 1.4 h, and 9.3 h, respectively. THP-adriamycin was rapidly taken up by blood cell components, with concentrations in red blood cells (RBCs), lymphocytes, and polymorphonuclear cells exceeding those in plasma. In all, <10% of the compound was eliminated in the urine within 24 h.

Pharmacokinetics and metabolism of β-2′-deoxythioguanosine and 6-thioguanine in man

SummaryResistance to the antileukemic agent 6-thioguanine (TG) inevitably develops in animal tumors. However, a new agent, β-2′-deoxythioguanosine (β-TGdR) can overcome TG resistance in animal tumor models and is therefore of potential clinical use. The pharmacokinetics of radiolabeled TG were compared with those of β-TGdR in patients with cancer after intravenous administration. [35S]-β-TGdR (5.4 mg/kg, 200 mg/m2, 200 μCi total) was administered to five patients; the radiolabel in the plasma declined with an initial half-life (t1/2) of 14 min and a terminal t1/2 of 19.3 h. Within 24 h, 65% of the radiolabel was excreted in the urine. In contrast, after administration of [35S]-6-TG (3.4 mg/kg, 125 mg/m2, 200 μCi total) the average initial t1/2 was 40 min while the terminal phase t1/2 was 28.9 h. Urinary excretion of the radiolabel was 75% of the dose 24 h after administration. Both thiopurines were rapidly and extensively degraded and excreted as 6-thioxanthine, inorganic sulfate, S-methyl-6 thioxanthine, and 6-thiouric acid in addition to other products. Small amounts of unchanged drug were also excreted. These studies suggest that β-TGdR is merely a latent form of TG.