Altered phenytoin clearance during intensive chemotherapy for acute lymphoblastic leukemia.
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Antineoplastic Combined Chemotherapy Protocols↗
Biomedical subjects
F M Balis
Publications and source records attributed to F M Balis.
Pharmacologic considerations in the treatment of acute lymphoblastic leukemia.
Great strides have been made in the chemotherapy of childhood ALL over the past three decades. Principles and concepts learned from early successes in treating this disease subsequently have been applied to the treatment of other pediatric cancers and adult malignancies. Because of the prominent role of chemotherapy in the treatment of ALL, a clear understanding of the clinical pharmacology of the antileukemic drugs is essential. This article reviews issues relating to the clinical pharmacology of the anticancer drugs that are commonly used in the treatment of acute lymphoblastic leukemia.
Antineoplastic Agents↗
Bioavailability of low-dose vs high-dose 6-mercaptopurine.
The bioavailability of oral 6-mercaptopurine (6MP) at standard doses is very low, largely as a result of extensive first-pass metabolism by xanthine oxidase. Fewer than one third of patients achieve 6MP plasma concentrations known to be cytocidal in vitro (greater than 1 mumol/L). Studies in vitro have suggested that first-pass metabolism can be saturated at higher doses of 6MP. To determine whether saturation occurs in vivo at clinically used doses and whether bioavailability can be enhanced by increasing the dose, the bioavailability of different doses of 6MP was studied first in rhesus monkeys and then in children with acute lymphoblastic leukemia in remission. In monkeys a higher dose of 6MP resulted in enhanced bioavailability, whereas in patients the mean relative bioavailability at the higher dose was significantly less. However, all patients achieved cytocidal (greater than 1 to 10 mumol/L) plasma concentrations at the higher dose without manifesting significant clinical toxicity. Therefore cytocidal levels of 6MP can be achieved in patients with oral 6MP without the risk of unexpectedly high levels caused by saturation of first-pass metabolism.
Adolescent↗
Fluconazole penetration into cerebrospinal fluid: implications for treating fungal infections of the central nervous system.
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Animals↗
Bioavailability of oral trimetrexate in patients with acquired immunodeficiency syndrome.
The combination of the lipophilic antifolate trimetrexate and the rescue agent leucovorin has shown promise in the treatment of Pneumocystis carinii pneumonia in patients with acquired immunodeficiency syndrome. The pharmacokinetic behavior of trimetrexate administered either by intravenous bolus or orally was studied in six patients with acquired immunodeficiency syndrome with a reversed-phase high-pressure liquid chromatography assay. The mean clearance following bolus injection was 38 ml/min per m2, with a range of 15 to 55 ml/min per m2. The postdistributive half-life ranged from 6 to 16 h. With oral administration, the mean bioavailability was 44% (range, 19 to 67%). An oral dose of 60 mg/m2 (162 mumol/m2) resulted in concentrations in plasma that approximated those achieved with a 30-mg/m2 (81-mumol/m2) intravenous dose. The toxicity of this combination regimen was minimal. It appears that the oral route is a practical route of administration for trimetrexate in patients with acquired immunodeficiency syndrome requiring long-term outpatient treatment or prophylaxis for P. carinii pneumonia.
Acquired Immunodeficiency Syndrome↗
Pharmacokinetics of subcutaneous methotrexate.
The pharmacokinetics of subcutaneously administered methotrexate was studied as a parenteral alternative to oral administration. An initial feasibility study was performed in Rhesus monkeys comparing the subcutaneous route to intravenous (IV) injection and oral administration. The subcutaneous dose was completely absorbed and a sustained-release effect was observed when compared with the IV dose. No local or systemic toxicities resulted from subcutaneous methotrexate in the animals. Twelve children with acute lymphoblastic leukemia on maintenance therapy protocols prescribing either 7.5 mg/m2 biweekly or 40 mg/m2 weekly were also monitored after both a subcutaneous and an oral dose of methotrexate. Four children at the higher dosage level were also studied after an equal IV dose. The subcutaneous dose was again completely absorbed in these children at both dose levels, whereas the oral dose, which produced comparable plasma drug concentrations at the lower dosage level, resulted in a total drug exposure (area under the plasma concentration-time curve) that was one third that of the equal subcutaneous dose at the higher dosage level. No local or systemic toxicity was attributed to the subcutaneous methotrexate. Subcutaneous administration of methotrexate is well tolerated and well absorbed and appears to overcome the problems associated with oral administration, including variable absorption and saturation of the absorption mechanism with increasing doses.
Absorption↗
Pyrimidine dideoxyribonucleosides: selectivity of penetration into cerebrospinal fluid.
Cerebrospinal fluid (CSF)/plasma ratios of 1 to 30% were obtained in rhesus monkeys for the 3'-azido- and 2',3'-dideoxy-analogs of thymidine, deoxycytidine and deoxyuridine. Penetration of thymidine and deoxyuridine analogs was much greater than for deoxycytidine analogs. Octanol/buffer partition coefficients varied more than 30-fold, but did not correlate with CSF entry. Plasma protein binding was insignificant for all compounds. The presence or absence of the azido group at position 3' did not appear to influence the extent of CSF penetration. Although we do not fully understand the mechanistic basis for the penetration of these nucleosides into the CSF, it is apparent that the structural specificity is related more closely to the nucleobase than the sugar. Based upon elimination rates from the CSF after direct intrathecal injection, the differences in net penetration are determined by influx rather than efflux processes.
Animals↗
Intrathecal administration of 4-hydroperoxycyclophosphamide in rhesus monkeys.
The preactivated cyclophosphamide analogue, 4-HC, does not require activation by hepatic microsomal enzymes to express its cytotoxic activity and therefore, unlike cyclophosphamide, may be useful for the regional therapy of cancer. In the present study, the pharmacokinetics and toxicology of 4-HC were studied following intraventricular administration of 0.4 mg to rhesus monkeys with chronic indwelling Ommaya reservoirs. 4-HC was measured in cerebrospinal fluid (CSF) and plasma with a high-performance liquid chromatography assay utilizing a fluorometric detector following derivatization with m-aminophenol. The mean peak level of 4-HC in ventricular CSF was 100 microM 5 min after administration. The drug was cleared rapidly and the elimination was monoexponential with a mean half-life of 22 min. The mean clearance from CSF (0.33 ml/min) was 10-fold higher than CSF bulk flow. The drug was distributed throughout the subarachnoid space with lumbar levels approaching ventricular levels by 60 min. Neither acute nor chronic neurotoxicity or systemic toxicity was observed during the 6-wk observation period. Concentrations of 4-HC demonstrated to be cytocidal in vitro against human breast cancer, lymphoid leukemia, and rhabdomyosarcoma were readily achieved in CSF following intraventricular administration. This study demonstrates that intraventricular therapy with 4-HC is feasible and suggests that further study of this approach in the clinical setting should be considered.
Animals↗
Pediatric phase I trial and pharmacokinetic study of trimetrexate.
Trimetrexate, a new nonclassical antifolate, was evaluated in a phase I trial in children with refractory cancer including nine with acute leukemia and 21 with solid tumors. The drug was administered as an i.v. bolus injection weekly for three doses, and courses were repeated every 28 days. The dose ranged from 35 to 145 mg/m2. Thirty patients who received a total of 33 courses were evaluable for toxicity, including 19 who were evaluable for hematological toxicity. The maximally tolerated dose for patients with a solid tumor and leukemia was 110 mg/m2. The dose-limiting toxicities were myelosuppression, mucositis and a pruritic, diffuse maculopapular rash. Other side effects observed included transient, mild elevations of serum transaminases, mild nausea and vomiting, and a local phlebitis at the site of injection at higher dose levels. A single patient with delayed drug clearance had evidence of renal toxicity with a transient increase in serum creatinine. The pharmacokinetics of trimetrexate were studied in 25 patients over the entire dose range. There was considerable interpatient variability in total drug clearance (range 9.2 to 215 ml/min/m2) and half-life (2.1 to 20 h). There was a suggestion of a correlation between plasma concentration at 24 h and the development of hematological toxicity at the highest dose level. Trimetrexate was cleared primarily by biotransformation with renal clearance accounting for only 10% of total clearance. Two metabolites of trimetrexate which inhibit the enzyme dihydrofolate reductase were identified in the urine. One of these appears to be a glucuronide conjugate.
Adolescent↗
The effect of methotrexate on the bioavailability of oral 6-mercaptopurine.
Fourteen children (aged 3 to 14 years) with average-risk acute lymphoblastic leukemia were studied after an oral dose of 6-mercaptopurine (6-MP) (75 mg/m2) administered alone and, on the next day, concurrently with oral methotrexate (20 mg/m2). When 6-MP was administered alone, both the peak plasma concentration (15 to 150 ng X ml-1) and the AUC (36 to 340 ng X ml-1 X hr) were highly variable. Concurrent methotrexate resulted in a 31% increase in the AUC (P less than 0.01) and a 26% increase in peak plasma levels (P less than 0.05) of 6-MP. The AUC of methotrexate correlated with the degree of increase in 6-MP plasma concentrations. These findings are consistent with previous in vitro studies demonstrating that methotrexate is an inhibitor of xanthine oxidase, the enzyme that catabolizes 6-MP to the inactive metabolite thiouric acid. Although the increases in 6-MP AUC and peak plasma concentrations resulting from concurrent methotrexate administration were statistically significant, this interaction is probably not clinically significant at standard low oral doses of methotrexate in light of the wide interpatient variability in these pharmacokinetic parameters of 6-MP.
Administration, Oral↗
Folate and methotrexate polyglutamate tissue levels in rhesus monkeys following chronic low-dose methotrexate.
Methotrexate (MTX), a mainstay in the treatment of acute lymphoblastic leukemia, is associated with both hepatic and neurologic toxicity. Like a folate, MTX is metabolized to polyglutamated derivatives (MTXGlun) with long intracellular half-lives. These metabolites may contribute to MTX toxicity through a direct effect on cellular metabolism or indirectly through a perturbation of folate homeostasis. To better define the effects of chronic MTX treatment, tissue levels of MTX, MTXGlun, and folate were measured in three monkeys treated with weekly intramuscular MTX for 1 year. Greater than 80% of the total tissue MTX found was in the form of polyglutamated derivatives. Most of these derivatives were MTXGlu3-5 but Glu6-7 were easily detectable. Total tissue folates were measured in liver, kidney, brain and testis with MTX treated animals having a 90% loss of total folate in brain tissue. This is of special interest since inborn errors of folate metabolism are often associated with severe neurologic abnormalities.
Animals↗
Differences in cerebrospinal fluid penetration of corticosteroids: possible relationship to the prevention of meningeal leukemia.
The disposition of the synthetic corticosteroids, dexamethasone and prednisolone, in CSF was evaluated following bolus intravenous (IV) and intrathecal (IT) injection in a nonhuman primate model. Steroid concentration in plasma and CSF was measured with a radioimmunoassay following celite column chromatography. The CSF to plasma ratios of dexamethasone and prednisolone following IV bolus administration were 0.15 +/- 0.02 and 0.08 +/- 0.03, respectively. Although peak levels of the two steroids in the CSF reached equally potent levels when administered systemically in equipotent doses, the half-life of prednisolone in the CSF was shorter. In addition, there was a significant difference in the plasma protein binding of the two steroids, which may account for the differences in their CSF pharmacokinetics. Dexamethasone was 70% protein bound over a wide concentration range, while the protein binding of prednisolone was concentration dependent, ranging from 60% at 10 mumol/L to 95% at 0.5 mumol/L and below. After the initial distribution phase in plasma, CSF concentrations of dexamethasone and prednisolone approximated free plasma concentrations, indicating that penetration into the CSF was limited primarily by protein binding. At the plasma concentrations achieved following oral administration of standard doses of prednisone in children, the prednisolone (the active metabolite) is greater than 90% protein bound. The proportionally higher free plasma levels of dexamethasone result in greater penetration into the CSF. These findings may explain the lower rates of meningeal leukemia observed in children receiving dexamethasone instead of prednisone for the treatment of acute lymphoblastic leukemia (ALL).
Animals↗
Stability of 5-fluorouracil in whole blood and plasma.
We studied the stability of 5-fluorouracil (5-FU) in plasma and whole blood kept at room temperature and on ice for 1 to 24 h. At room temperature, there was a steady loss of 94% of the parent drug over 24 h in whole blood and 52% in plasma. In the presence of an excess of uracil, 5-FU was stable for 24 h, suggesting that the loss of 5-FU is the result of enzymatic degradation. 5-FU is more stable in whole blood and plasma when samples are kept cold. For blood and plasma samples maintained on ice, the loss was only 30% and 10% of the parent drug in the respective samples over 24 h. Frozen plasma samples (-20 degrees C) were stable for five weeks. Blood specimens collected for quantifying 5-FU should be immediately placed on ice, and the plasma should be separated and frozen as promptly as possible.
Drug Stability↗
The pharmacology of orally administered chemotherapy. A reappraisal.
Rational treatment of pediatric malignancies requires a detailed knowledge of the clinical pharmacology of those antineoplastic agents used therapeutically. A number of different agents are administered by the oral route. Recently, the clinical pharmacology of 6-mercaptopurine (6-MP) and methotrexate (MTX), the two agents that are the mainstay of maintenance chemotherapy in acute lymphoblastic leukemia (ALL), were investigated. Studies of oral 6-MP indicate that, contrary to previous information, the bioavailability of this drug is relatively poor after oral administration, and that plasma 6-MP concentrations achieved after uniform oral dosing are highly variable. Similarly, study of the pharmacology of orally administered MTX indicates that there is little correlation between MTX dose and the peak serum level achieved. These findings suggest that some patients may not be exposed to adequate systemic concentrations of 6-MP and/or MTX after oral administration, and raise the possibility that the development of relapse in some patients with ALL may be the result of a pharmacologic failure of oral maintenance therapy. A comprehensive prospective study of the clinical pharmacology of MTX and 6-MP in patients with ALL undergoing maintenance chemotherapy is currently in progress.
Administration, Oral↗
The effect of amitriptyline on the central nervous system penetration of methotrexate.
The reported ability of amitriptyline to enhance the penetration of diffusion limited substances across the blood brain barrier was investigated. The CSF:plasma ratio of methotrexate in primates was not significantly altered by amitriptyline pretreatment. Nor was methotrexate plasma clearance altered.
Amitriptyline↗
The influence of route of administration on the hepatic uptake of methotrexate.
The present study was designed to determine if the hepatic toxicity of chronic low-dose methotrexate could be circumvented by administering the drug systemically, avoiding high initial hepatic drug exposure resulting from absorption of an oral dose into the portal circulation. Hepatic concentrations of methotrexate were determined in rats following chronic administration of 1 mg/kg by either the intraperitoneal (absorbed via the portal circulation) or subcutaneous route. Plasma drug profiles of methotrexate administered by the two routes were similar. The mean (+/- S.D.) hepatic methotrexate concentration following intraperitoneal administration was 3.12 +/- .47 nmol/gm wet weight and following subcutaneous administration it was 2.68 +/- .52 (p = .06). Renal methotrexate concentrations in the 2 groups were 1.23 +/- .27 and 1.26 +/- .49 nmol/gm wet weight, respectively (p = .88). The results of this study suggest that that oral administration does not lead to greater accumulation of methotrexate in the liver compared to systemic administration.
Animals↗
Influence of food intake on bioavailability of oral 6-mercaptopurine in children with acute lymphoblastic leukemia.
Plasma levels of 6-mercaptopurine (6-MP) were measured after oral administration in 17 children with acute lymphoblastic leukemia (ALL). In the fasting state or after a breakfast consisting of 250 ml milk and 50 g biscuits, 6-MP was administered at a dose of 75 mg/m2. In patients studied in a fasting state, the mean time to plasma peak (tmax) level was 1.2 h, whereas in patient studied after breakfast the mean tmax was 2.3 h. This difference is statistically significant (p less than 0.001). Moreover, the 6-MP peak plasma concentration (cmax) and the areas under the plasma concentration time curves (AUC) were significantly reduced when the drug was administered after breakfast. The mean Cmax +/- SD were 0.98 +/- 0.54 microM and 0.63 +/- 0.48 microM, respectively (p less than 0.05). The mean 6-MP AUC +/- SD in patients studied in a fasting state and after breakfast were 143 +/- 69 microM min and 105 +/- 68 microM, respectively (p less than 0.01). These results indicated that 6-MP should be taken in a fasting state to optimize drug absorption in children undergoing chemotherapy for ALL.
Administration, Oral↗
Pharmacokinetics of trimetrexate (NSC 352122) in monkeys.
The pharmacokinetics of trimetrexate was studied in Rhesus monkeys following i.v. bolus, continuous i.v. infusion, oral, and subcutaneous administration. Two methods were used to measure drug concentration in plasma, cerebrospinal fluid (CSF), and urine: the dihydrofolate reductase inhibition assay, and a reverse phase high-pressure liquid chromatography assay. The pharmacokinetic behavior of trimetrexate was characterized by triexponential plasma disappearance, elimination primarily by biotransformation, substantial plasma protein binding, poor CSF penetration, and limited oral bioavailability. Methotrexate, administered in an equimolar dose for comparison, was cleared more rapidly from plasma than was trimetrexate. Trimetrexate concentration remained above 0.1 microM 3-fold longer. In contrast to methotrexate, which is cleared almost exclusively by renal excretion, renal clearance of trimetrexate accounted for less than 5% of total clearance. A significant discrepancy was observed in plasma and urine trimetrexate concentrations measured by the two assay methods. The dihydrofolate reductase inhibition assay gave results approximately 2- to 4-fold higher in plasma. Two metabolites of trimetrexate which inhibit dihydrofolate reductase were identified in urine (one was also found in plasma) and appear to account for the different results obtained by the two assays. These metabolites would probably also interfere with the competitive protein binding assay currently being used to measure trimetrexate in ongoing phase I trials.
Animals↗