Lopinavir/ritonavir reduces bupropion plasma concentrations in healthy subjects.

Limited data are available about the effect of steady-state lopinavir and ritonavir (LPV/r) on bupropion pharmacokinetics. As patients may benefit by using these two agents in combination, this study determined the extent and direction of this drug-drug interaction. Twelve healthy volunteers received a single 100 mg dose of sustained-release bupropion before and after 2 weeks of treatment with LPV/r 400 mg/100 mg twice daily. Pharmacokinetics profiles were determined on days 1 and 30 for bupropion and hydroxybupropion and days 29 and 30 for LPV/r. LPV/r administration significantly decreased bupropion maximum plasma concentration (C(max)) by 57% (90% confidence interval (CI), 38-76%; P<0.01) and area under the curve (AUC) infinity by 57% (90% CI, 32-83%; P<0.01). Hydroxybupropion C(max) and AUC infinity decreased by 31% (90% CI, 7-55%; P<0.01) and by 50% (90% CI, 34-65%; P<0.01), respectively. No significant changes in the pharmacokinetics of LPV/r were found following administration of a single dose of bupropion. Concurrent use of LPV/r and bupropion resulted in decreased exposure to bupropion and its active metabolite hydroxybupropion that may necessitate as much as a 100% dose increase of bupropion. A probable mechanism for this interaction is the concurrent induction of cytochrome P450 2B6 and UDP-glucuronosyltransferase enzymes. LPV/r exposure is unaffected by a single dose of bupropion.

Phase I clinical and pharmacokinetic study of 4'-(9-acridinylamino)-methanesulfon-m-anisidide in children with cancer.

Forty-one pediatric patients with advanced cancer (24 with acute leukemia and 17 with diverse solid tumors) received 74 courses of therapy with a new chemotherapeutic agent, 4'-(9-acridinylamino)methanesulfon-m-anisidide (AMSA: NSC 249992). Treatments were given by slow i.v. injection daily for five days every two to three weeks. In patients with leukemia: (a) dosages were escalated from 1.3 to 150 mg/sq m/day; (b) toxicity in the form of stomatitis, vomiting, and phlebitis occurred at dosage levels of 125 to 150 mg/sq m/day; and (c) oncolytic effects were observed in 13 of 24 patients. In patients with solid tumors: (a) dosages were escalated from 5 to 50 mg/sq m/day; (b) toxicity (stomatitis, myelosuppression, and phlebitis) occurred at the dosage level of 50 mg/sq m/day; and (c) no oncolytic responses were noted. Serum concentrations of total and free AMSA were assayed by a fluorescence technique and declined in a biphasic manner with free AMSA declining more rapidly than total AMSA. Dosages of greater than 100 mg/sq m/day were required to maintain serum concentrations of total and free AMSA greater than 0.2 microM for the entire five-day schedule. The results suggest that maximum tolerated dosages of AMSA may differ in children with leukemia and solid tumors; however, hematopoietic toxicity could not be fully evaluated in the patients with leukemia. AMSA has clear antileukemic activity that warrants future Phase II trials.

Age-dependent cyclosporine: pharmacokinetics in marrow transplant recipients.

We evaluated the effect of age on cyclosporine pharmacokinetics in 69 nonobese patients aged 10 months to 56 years (median 22 years) undergoing allogeneic bone marrow transplantation for treatment of aplastic anemia or hematologic malignancy. Cyclosporine pharmacokinetics were studied during the first 2 posttransplant weeks after an intravenous dose of 2.6 to 3.5 mg/kg. Serum cyclosporine concentrations were measured by HPLC. Cyclosporine concentration-time data were fitted to a two-compartment model with a nonlinear regression program. There was a significant inverse linear correlation between age and both total systemic clearance (CL) (r = 0.42; P less than 0.001) and volume of distribution at steady-state (Vss) (r = 0.33; P less than 0.01). Mean (+/- SE) cyclosporine CL was 82 +/- 21, 45 +/- 5, 38 +/- 9, 44 +/- 8, and 20 +/- 3 ml/min/kg and mean cyclosporine Vss was 34 +/- 11, 28 +/- 10, 15 +/- 4, 14 +/- 5, and 4.7 +/- 0.7 L/kg in patients 0 to 10 (n = 12), 11 to 20 (n = 19), 21 to 30 (n = 12), 31 to 40 (n = 17), and greater than 40 (n = 9) years old, respectively. Patients 0 to 10 years old had a significantly higher cyclosporine CL than those 11 to 40 or greater than 40 years old and also had a significantly larger Vss than those greater than 40 yrs old (P less than 0.05). Age-related differences in CL or Vss were also observed when these parameters were normalized by body surface area.(ABSTRACT TRUNCATED AT 250 WORDS)

Bleomycin disposition in children with cancer.

Bleomycin kinetics were determined in 14 children after intravenous bolus and prolonged infusion doses. Plasma and urine bleomycin concentrations were determined by radioimmunoassay. After intravenous bolus, bleomycin concentrations were adequately described by a two-compartment open model with a mean t1/2 alpha and t1/2 beta of 0.3 +/- 0.1 and 3.2 +/- 0.7 hr (mean +/- SEM). Volume of the central compartment and volume of distribution at steady-state (Vss) were 4.3 +/- 0.5 and 9.9 +/- 1.1 l/m2. Total plasma (CLT) and renal (CLR) clearance were 51.8 +/- 6.1 and 33.5 +/- 2.4 ml/min/m2. Three intravenous bolus courses were given to two patients who received more than four courses of cisplatin (greater than 300 mg/m2); CLT and CLR for these courses were 18.0 +/- 3.3 and 8.2 ml/min/m2. Conversely, children under 3 yr old eliminated bleomycin more rapidly than older children. Decline in bleomycin concentrations after seven 24- or 48-hr intravenous infusions was described by a one-compartment model. Mean values for plasma t1/2, Vss, CLT, and CLR were 2.1 +/- 0.1 hr, 11.0 +/- 2.6 l/m2, 57.1 +/- 13.5 ml/min/m2, and 33.2 +/- 6.4 ml/min/m2. One patient received his bleomycin infusion when ureteral obstruction was present; CLT and CLR for this course were 4.8 and 4.1 ml/min/m2. These data indicate that young children eliminate bleomycin more rapidly than older children and that children with impaired renal function may have prolonged elevations in plasma concentration due to reduced bleomycin clearance. Bleomycin disposition in older children is as in adults.

Pharmacokinetics of intravenous cyclosporine in bone marrow transplant patients. Comparison of two assay methods.

The influence of assay method on steady-state cyclosporine (CsA) pharmacokinetics was studied in 18 patients with leukemia or aplastic anemia undergoing allogeneic marrow transplantation who received i.v. CsA for prophylaxis or treatment of graft-versus-host disease. Since CsA is extensively metabolized and subject to biliary elimination, CsA courses were divided according to the presence (serum bilirubin greater than 2.0 mg/dl) or absence (serum bilirubin less than or equal to 1.2 mg/dl) of hepatic dysfunction. All patients had normal renal function. Serum CsA concentrations were measured concurrently by radioimmunoassay (RIA) and high-performance liquid chromatography (HPLC). Serum concentration-time data were analyzed by standard nonlinear regression methods. Systemic clearance (Cls) calculated from HPLC results was higher than that derived from RIA results, regardless of hepatic function (P less than 0.05). These data indicate that results obtained by RIA overestimate CSP concentrations, presumably because of the presence of crossreactive CSP metabolites. These differences can significantly affect derived pharmacokinetic parameters. Therefore, clinicians who make dosage recommendations based on pharmacokinetic parameters should consider the effect of assay method.

Marrow graft rejection and veno-occlusive disease of the liver in patients with aplastic anemia conditioned with cyclophosphamide and cyclosporine.

Based on studies in multiply transfused dogs showing that cyclosporine (CsA) pregrafting reduced the incidence of rejection, we treated 11 multiply transfused patients with severe aplastic anemia with CsA, 12.5-20 mg/kg/day i.m. on days -6 to -1, and cyclophosphamide, 50 mg/kg/day i.v. on days -5 to -2, followed on day 0 by a marrow graft from an HLA-identical sibling donor. Patients were not given additional infusions of buffy coat cells from their marrow donors. As postgrafting prophylaxis for graft-versus-host disease 10 patients were given CsA, 12.5 mg/kg/day orally, and one patient was given a standard regimen of intermittent methotrexate. Among 10 evaluable patients, 2 rejected their marrow grafts. Eight patients had sustained engraftment. Two of these developed severe veno-occlusive disease of the liver, a complication previously observed only in patients conditioned with total-body irradiation but not in more than 200 patients with aplastic anemia conditioned with cyclophosphamide without the addition of CsA. These data indicate that conditioning of patients with cyclophosphamide and concurrent CsA does not uniformly prevent graft rejection and can result in severe hepatic toxicity.

Pharmacodynamic studies of cyclosporine in marrow transplant recipients. A comparison of three assay methods.

We investigated the correlation between trough cyclosporine concentration in plasma measured by polyclonal fluorescence polarization immunoassay (FPIA) and polyclonal radioimmunoassay (RIA) or in whole blood measured by high-performance liquid chromatography (HPLC) and the risk of renal dysfunction or acute graft-versus-host disease in 29 patients undergoing allogeneic bone marrow transplantation for leukemia. The FPIA and RIA values were highly correlated (r = 0.93) and on the average CsA concentrations measured by FPIA were 1.56 times higher than those measured by RIA. Ten patients developed renal dysfunction and 10 developed grades II-IV acute GVHD. Although univariate analysis showed that plasma CsA concentrations measured by either FPIA or RIA were significantly correlated with renal dysfunction, the association was stronger with FPIA. Plasma CsA concentrations measured by FPIA but not RIA remained a significant risk factor for renal dysfunction in a multivariate relative risk model. Amphotericin therapy was significantly associated with renal dysfunction in the univariate analysis but not in the multivariate analysis. No significant associations were found between whole blood CsA or CsA M1 concentration, patients' age, gender, or CsA dose and the risk of renal dysfunction. None of the covariates analyzed significantly correlated with the development of acute GVHD. These data suggest that plasma CsA concentrations measured by nonspecific assays may more accurately correlate with renal dysfunction than whole-blood CsA concentrations measured by HPLC in marrow transplant recipients.

Blood cyclosporine pharmacokinetics in patients undergoing marrow transplantation. Influence of age, obesity, and hematocrit.

Blood cyclosporine pharmacokinetics were studied in 85 patients aged 1-52 (median: 22) years undergoing allogeneic bone marrow transplantation for the treatment of hematologic disease. Pharmacokinetic studies were carried out during the first two weeks posttransplant after an intravenous dose of 2.1-4.4 mg/kg. Whole-blood cyclosporine concentrations were measured by high-performance liquid chromatography. Multiple stepwise regression analysis indicated that age (P less than 0.001) and hematocrit (P less than 0.05) correlated with cyclosporine clearance (CL) while steady-state volume of distribution (Vss) did not correlate with any of the factors studied. Cyclosporine CL significantly differed among nonobese patients in different age groups; patients less than or equal to 10 years old had a higher mean CL (13.1 ml/min/kg) than patients 11-20, 21-30, 31-40, or greater than 40 years old (mean CL: 8.5-10.3 ml/min/kg) (P less than 0.05). No significant differences in cyclosporine CL and Vss were observed between obese (greater than 125% ideal body weight) patients and age-matched nonobese patients. Hematocrit values (range: 24-39) were inversely correlated with cyclosporine CL, which suggests that red blood cells function as important ligands in cyclosporine binding. These results show that blood cyclosporine CL is higher in marrow transplant recipients than in solid organ transplant recipients and that these differences may be related to lower hematocrits in marrow transplant recipients compared with solid organ transplant recipients. When compared with previously published serum cyclosporine CL data, our findings suggest that age-related changes in CL are primarily related to changes in plasma protein binding and that obesity does not significantly alter cyclosporine CL and Vss.

Monitoring of cyclosporine therapy with in vitro biological assays.

We examined the correlation between cyclosporine (CsA) levels and in vitro assays of immune function and hematopoiesis. Mixed lymphocyte reaction (MLR), mitogen responses, suppressor cell (SC), cell-mediated lympholysis (CML), and erythroid colony (EC) assays were studied in dogs, and in vitro megakaryocytopoiesis was studied in mice. Serum CsA concentrations were measured by radioimmunoassay. After oral or intramuscular CsA dosing, lymphocyte proliferation, as measured by MLR, inversely correlated with in vivo serum CsA concentration. MLR responses decreased rapidly, and nearly complete inhibition coincided with peak CsA levels. While CsA concentration-related suppression of lymphocyte stimulation was also observed in mitogen-stimulated cultures, results were less predictable and similar to results with in vitro CsA addition, and higher serum CsA levels were required to achieve comparable suppression. In vivo serum or in vitro CsA levels greater than 300 ng/ml completely inhibited the development of cytotoxic effector cells but had no measureable effect on the expression of suppressor cells in the same cultures. Furthermore, CsA serum also caused concentration-related inhibition of EC growth. The addition of human embryonic kidney-conditioned medium, however, abrogated CsA-related inhibition of EC growth, which suggested that CsA indirectly inhibited EC growth, presumably by interfering with CsA-sensitive accessory cells. This was supported by studies in an in vitro model of murine megakaryocytopoiesis. In normal conditioned medium, megakaryocyte colonies were unaffected by the presence of CsA. However, when cells were cultured in conditioned medium prepared in the presence of CsA, profound inhibition of megakaryocyte growth was observed. These studies show that biologic assays can be used reliably to measure concentration-related changes in immunosuppressive activity of CsA. Further clinical studies are needed to evaluate the usefulness of pharmacodynamic monitoring of CsA therapy.

Correlation of serum cyclosporine concentration with renal dysfunction in marrow transplant recipients.

We retrospectively analyzed the relationship of serum cyclosporine concentration to renal dysfunction in 63 marrow transplant recipients who received cyclosporine for prophylaxis of acute graft-versus-host disease. Patients were divided into three groups according to their mean trough cyclosporine concentration for the first 28 days of therapy: less than 150, 150-250, and greater than 250 ng/ml. Baseline renal function and exposure to nephrotoxic antibiotics was comparable in the three groups. Renal dysfunction was defined as doubling of baseline serum creatinine. The likelihood of developing renal dysfunction was analyzed with Kaplan-Meier product limit estimates. The log-rank test was used to compare the three groups. Fifty-four (86%) of the patients developed renal dysfunction. The incidence of renal dysfunction was 73%, 95%, and 100%, and it developed at a median of 46, 29, and 20 days in patients with a mean trough concentration of less than 150, 150-250, and greater than 250 ng/ml, respectively (P less than 0.001). Eight of the nine patients who did not develop renal dysfunction had a mean trough concentration of less than 150 ng/ml. These data indicate that the incidence and the rate of development of renal dysfunction are related to serum cyclosporine concentration.

Pharmacokinetic drug interactions with cyclosporin (Part II).

Part I of this article, which appeared in the previous issue of the Journal, considered the potential mechanisms of drug interactions with cyclosporin, and divided the interacting drugs into 2 categories. Drugs that decrease cyclosporin concentrations (e.g. anti-convulsants, rifampicin, etc.) were dealt with first; the authors then moved on to consider the second category, those that increase cyclosporin concentration (macrolide antibiotics, azole antifungal drugs). Part II continues the survey of this category.

Pharmacokinetic drug interactions with cyclosporin (Part I).

This article reviews the reported pharmacokinetic interactions between cyclosporin and other drugs. Both rifampicin and the majority of anticonvulsants can decrease cyclosporin concentrations to levels that are at or below the limit of detection for most assays. There have been no reports of any interaction between valproic acid and cyclosporin. Other drugs that have been reported to decrease cyclosporin concentration include sulfadimidine and trimethoprim, nafcillin and octreotide. Erythromycin, ketoconazole and some calcium channel blockers have been clearly shown to increase the concentration of cyclosporin. Other less well documented interactions have been reported with other macrolide antibiotics, other azole antifungal drugs, high dose methylprednisolone, metoclopramide, fluoroquinolones, imipenem/cilastatin, oral contraceptives/danazol, sulindac, methyltestosterone, colchicine, acetazolamide, alcohol and cimetidine. Although the most commonly reported mechanism is inhibition of cyclosporin metabolism, there is increasing evidence that erythromycin, metoclopramide and probably other drugs increase the bioavailability of oral cyclosporin. Two calcium channel blockers which have not been reported to interact with cyclosporin are nifedipine and nitrendipine. With increasing use of cyclosporin, the number of drugs reported to interact will rise. Prudent clinicians should monitor the concentration of this agent more frequently when another drug is added or discontinued and cyclosporin dosage should be adjusted when appropriate. Sustained changes in cyclosporin concentration can result in graft rejection (or graft-versus-host disease) or renal toxicity. Further studies are needed to determine the mechanism of most of these interactions.

A model for dosing gentamicin in children and adolescents that adjusts for tissue accumulation with continuous dosing.

The pharmacokinetics of gentamicin were evaluated in 50 children and adolescents during a multiple dose course of therapy. Parameters of a 2-compartment pharmacokinetic model were derived from serial serum concentrations and urinary excretion rates measured for up to 11 days following the last dose of gentamicin administered to 10 of these patients. These parameters were used to simulate changes in serum concentrations and half-lives that would occur during a standard 6-hour dosing interval with continuous dosing. The data indicated that the half-life for decline in serum concentrations after the first dose was 76 +/- 8% of the half-life at steady-state, and that the half-life after the fourth dose exceeded 90% of the steady-state half-life. These underestimations of the steady-state serum half-life were incorporated into a 1-compartment model to simulate steady-state peak and nadir serum concentrations by using pharmacokinetic parameters measured after the first dose of gentamicin administered to 40 patients. Steady-state serum concentrations predicted by the true 1-compartment model and by the adjusted model were compared with concentrations measured at steady-state. The concentrations predicted by the former model were significantly different from and consistently less than measured concentrations. Concentrations predicted by the adjusted model were not significantly different from concentrations measured at steady-state. These data indicate that the new model offers a simple and more accurate method of simulating steady-state concentrations from pharmacokinetil for individualising therapy.

Economic analysis of four triple regimens for the treatment of Helicobacter pylori-related peptic ulcer disease in in-patient and out-patient settings in Hong Kong.

BACKGROUND: One-week triple regimens have been shown to be effective for the treatment of Helicobacter pylori-related peptic ulcer disease. AIM: To conduct an economic analysis of four triple regimens for the treatment of H. pylori-related peptic ulcer disease from the perspective of a public health organization in Hong Kong. METHODS: Records of 200 patients with H. pylori-related peptic ulcer disease, who had previously participated in a randomized comparison of ranitidine bismuth citrate (RBC) with amoxicillin and clarithromycin (RAC), omeprazole with amoxicillin and clarithromycin (OAC), RBC with metronidazole and tetracycline (RMT), or, colloidal bismuth subcitrate with metronidazole and tetracycline (BMT) in either in-patient or out-patient setting were reviewed. RESULTS: Fifty patients were excluded because of incomplete documentation or lack of peptic ulcer. In the out-patient group (n=72), the median direct costs of the RAC group (HK $ 5094) were lower those of the BMT (HK $ 5400), RMT (HK $ 5394), or OAC (HK $ 5440) groups, but the difference was significant only between the RAC and BMT groups (P < 0.05). In the in-patient group (n=78), the median direct costs of the RMT group (HK $ 8524) were significantly lower than those of the OAC (HK $ 13 871) and RAC (HK $ 12 092) groups (P < 0.05), but were similar to those of the BMT group (HK $ 8758). CONCLUSIONS: RAC and RMT are the least costly regimens for out-patient and in-patient treatment, respectively, of H. pylori-related peptic ulcer disease in Hong Kong.

Monitoring cyclosporin concentrations in marrow transplant recipients: comparison of two assay methods.

Renal dysfunction is the major dose-limiting toxicity associated with cyclosporin therapy. We have previously shown in patients undergoing allogeneic bone marrow transplantation that serum cyclosporin concentrations, as measured by radioimmunoassay (RIA), correlate significantly with the development of renal dysfunction. However, since the RIA measures both parent drug and metabolites, the relative role of each in the development of nephrotoxicity could not be determined. Therefore, we re-measured cyclosporin concentrations in the same serum samples by high-performance liquid chromatography (h.p.l.c.). Serum cyclosporin concentrations of less than 50, 50-100 and greater than 100 ng/ml, as measured by h.p.l.c., were considered equivalent to cyclosporin concentrations of less than 150, 150-250 and greater than 250 ng/ml, as measured by RIA. Contrary to results by RIA, cyclosporin concentrations measured by h.p.l.c. did not significantly correlate with renal dysfunction, which suggests that measurement of serum cyclosporin concentrations by h.p.l.c. provides no clinical advantage to RIA for monitoring cyclosporin concentrations to prevent renal dysfunction.

Minimal risk of chronic renal dysfunction in marrow transplant recipients treated with cyclosporine for 6 months.

To determine whether 6 months of cyclosporine therapy is associated with chronic renal dysfunction, we evaluated serum creatinine concentrations 1 year post-transplant in 82 marrow transplant recipients randomized to receive either cyclosporine (n = 40) or methotrexate (n = 42) as graft-versus-host disease (GVHD) prophylaxis. Nine patients in the methotrexate group were later given cyclosporine as treatment for acute or chronic GVHD (methotrexate----cyclosporine). Cyclosporine prophylaxis was started on the day before marrow infusion, given at full doses until day 50, then gradually tapered and discontinued by day 180. Methotrexate prophylaxis was started on day 1 and given intermittently until day 102. Patients in the cyclosporine and methotrexate----cyclosporine groups had significantly higher mean serum creatinine values during the first 100 days post-transplant than methotrexate-treated patients, but by 1 year mean serum creatinine values were not significantly different between the three groups. Serum creatinine values at 1 year were also not significantly different from baseline values in each of the groups. None of the patients who had their cyclosporine discontinued by day 180 developed chronic renal dysfunction, defined as a doubling of the baseline serum creatinine at 1 year. We conclude that chronic renal dysfunction occurs rarely in marrow transplant recipients treated with 6 months of cyclosporine and when it does occur, it appears to have minimal clinical significance.

Topotecan-filgrastim combination is an effective regimen for mobilizing peripheral blood stem cells.

We compared the efficacy, toxicity, and cost of topotecan-filgrastim and filgrastim alone for mobilizing peripheral blood stem cells (PBSCs) in 24 consecutive pediatric patients with newly diagnosed medulloblastoma. PBSCs were mobilized with an upfront window of topotecan-filgrastim for 11 high-risk patients (residual tumor > or =1.5 cm2 after resection; metastases limited to neuraxis) and with filgrastim alone for 13 average-risk patients. All patients subsequently underwent craniospinal irradiation and four courses of high-dose chemotherapy with stem cell rescue. Target yields of CD34+ cells (> or =8 x 10(6)/kg) were obtained with only one apheresis procedure for each of the 11 patients treated with topotecan-filgrastim, but with a mean of 2.3 apheresis procedures for only six (46%) of the 13 patients treated with filgrastim alone (P = 0.0059). The median peak and median total yield of CD34+ cells were six-fold higher for the topotecan-filgrastim group (328/microl and 21.5 x 10(6)/kg, respectively) than for the filgrastim group (54/microl and 3.7 x 10(6)/kg, respectively). Mean times to neutrophil and platelet engraftment were similar. Myelosuppression was the only grade 4 toxicity associated with topotecan-filgrastim mobilization and lasted a median of 5 days. Compared with filgrastim mobilization, topotecan-filgrastim mobilization resulted in a mean cost saving of $3966 per patient. Topotecan-filgrastim is an efficacious, minimally toxic, and cost-saving combination for PBSC mobilization.

Renal cyclosporine clearance in marrow transplant recipients: age-related variation.

Cyclosporine is extensively metabolized in the liver and is subject to biliary elimination. Although only a small amount of the drug is eliminated unchanged in the urine, urine concentrations of the drug are much higher than blood or serum concentrations known to be associated with renal toxicity. Renal clearance (CL) of cyclosporine may be a sensitive correlate of nephrotoxicity, but renal CL studies of cyclosporine have not been reported in transplant patients. Therefore, we studied the renal CL of cyclosporine in 21 patients (median age, 27 yr) with hematologic malignancies undergoing allogeneic bone marrow transplantation. All patients received cyclosporine for prophylaxis or treatment of acute graft vs host disease. At the time of the study, all patients had normal renal function, as determined by serum creatinine concentration. Urine and serum cyclosporine concentrations were measured by high-performance liquid chromatography. Renal cyclosporine CL in different patients ranged from 1.8 to 79.8 mL/min. However, serial renal CL studies performed one week apart in two patients showed minimal intrapatient variability. Patients 25 years old or younger had a higher mean renal cyclosporine CL (39.7 mL/min) than older patients (17.9 mL/min) (P less than .05). These data show that renal cyclosporine CL is related to age and that renal CL in marrow transplant recipients is higher than the reported mean value in non-marrow-transplant patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Cisplatin disposition in children and adolescents with cancer.

The disposition of cisplatin was evaluated in 28 children and adolescents with cancer, as part of a phase II clinical trial. Patients received either 30 mg/m2 (11) or 90 mg/m2 (17) of cisplatin as a 6-h IV infusion. Serum samples and divided urine collections were obtained over 48 h following completion of the cisplatin infusion, and were assayed in duplicate for total platinum by atomic absorption spectrophotometry. Serum samples obtained up to 4 h after three cisplatin infusions were assayed for parent (free) cisplatin following ultrafiltration. The mean (+/- SE) elimination half-life of free cisplatin in serum was 1.3 (+/- 0.4) h. Serial serum concentrations of total platinum following 90 mg/m2 dosages were adequately described by a biexponential equation. The mean (+/- SE) serum T 1/2 alpha of total platinum was 0.42 (+/- 0.10) h and the mean (+/- SE) T 1/2 beta was 44.43 (+/- 8.24) h. The intercompartment distribution rate constants of a two-compartment kinetic model indicate extensive tissue accumulation of total platinum, with a rate of transport into tissue compartments (K12) that is about six times the rate of transport out of tissues (K21). The mean (+/- SE) renal clearance of total platinum from 0-3 h was 37.36 (+/- 11.96) ml/min/m2 and 35.8 (+/- 13.6) ml/min/m2 for the 30 mg/m2 and 90 mg/m2 groups, respectively. This value decreased to 3.25 (+/- 0.94) and 2.16 (+/- 0.4) ml/min/m2 for the two groups by the 6-12 h interval, and remained between 1 and 3 ml/min/m2 for the duration of the observation period. The ratio of total platinum clearance to creatinine clearance decreased significantly (P less than 0.05) beginning 3 h post-infusion. The change in renal clearance of total platinum is apparently a function of two independent first-order processes for renal clearance of parent drug and cisplatin metabolites.

Clinical pharmacology of bleomycin and cisplatin.

Bleomycin (Blenoxane) and cisplatin (Platinol) are two anticancer drugs with activity for head and neck tumors. Introduced into clinical use in the past ten years, bleomycin is used primarily in the chemotherapy of squamous cell carcinomas, lymphomas, and testicular carcinoma, while cisplatin is effective against testicular and ovarian carcinoma, head and neck cancer, bladder cancer, and neuroblastoma. Bleomycin is rapidly excreted renally (T 1/2 beta = 2-4 hr) although enzymatic inactivation also occurs in many tissues. Cisplatin is nonenzymatically converted to highly protein-bound metabolites, which then undergo renal elimination, but total body clearance occurs much more slowly than with bleomycin (T 1/2 beta = 40-50 hr). Both agents have acute and chronic toxicities; the acute toxicities are generally reversible but cause a great deal of patient discomfort, while the chronic toxicities are often irreversible and dose-limiting. For bleomycin, the acute toxicities are mucocutaneous and pyretic, while severe nausea and vomiting represent the major acute toxicities of cisplatin therapy. Cumulative dose-related pulmonary toxicity is the most serious chronic toxicity of bleomycin. The clinical, radiographic, and pathologic presentations are nonspecific, although identification of high-risk patients may be possible with serial pulmonary function tests. Cumulative nephrotoxicity occurs with cisplatin use and its incidence and severity can be reduced by maintaining adequate hydration and diuresis during and following administration of the drug.