SEARCH · PubMed Health

Results for “Topotecan”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources

PubMed1998

Phenytoin alters the disposition of topotecan and N-desmethyl topotecan in a patient with medulloblastoma.

Topotecan undergoes both renal and hepatic elimination, with topotecan urinary recovery ranging from 60 to 70%. We evaluated the potential of phenytoin to alter the disposition of topotecan and its N-desmethyl metabolite. A 5-year-old child with high-risk medulloblastoma received the first course of topotecan with phenytoin and the second course without phenytoin. For both courses, topotecan doses were adjusted to achieve a target topotecan lactone plasma area under the curve (AUC). Serial plasma samples were obtained, and lactone and total plasma concentrations of topotecan, as well as total plasma and cerebrospinal fluid concentrations of N-desmethyl topotecan, were measured by high-performance liquid chromatography. Phenytoin coadministration increased lactone and total topotecan clearance from 43.4 +/- 1.9 L/h/m2 to 62.9 +/- 6.4 L/h/m2, and 20.8 +/- 2.8 L/h/m2 to 30.6 +/- 4.1 L/h/m2, respectively (P < 0.05). Concomitant phenytoin increased the plasma AUC of total N-desmethyl topotecan from 7.5 +/- 0.68 ng/ml x h to 16.3 +/- 0.53 ng/ml x h (P < 0.05) at plasma AUC of total topotecan of 226.0 +/- 5.5 ng/ml x h and 240.9 +/- 39.8 ng/ml x h, respectively. N-Desmethyl topotecan penetrated into the cerebrospinal fluid (0.12 +/- 0.01). The patient experienced no grade 3 or 4 toxicity. These are the first data documenting altered topotecan and N-desmethyl topotecan disposition when coadministered with phenytoin and suggests that topotecan may undergo further hepatic metabolism. Although there is an increase in exposure to the active N-desmethyl topotecan metabolite, it is less than the decrease in exposure to topotecan lactone. Therefore, patients concomitantly administered phenytoin may require an increase in topotecan dose to achieve a similar pharmacological effect as a patient not receiving phenytoin.

Anticonvulsants↗

PubMedDate not supplied

Novobiocin sensitizes BCRP/MXR/ABCP overexpressing topotecan-resistant human breast carcinoma cells to topotecan and mitoxantrone.

BACKGROUND: Novobiocin was shown to sensitize cancer cells to etoposide and alkylating agents. Human breast carcinoma cells exposed to topotecan (MCF7/TPT300 cells) developed resistance to both mitoxantrone and topotecan. An ATP-binding cassette family protein BCRP/MXR/ABCP was overexpressed in MCF7/TPT300 cells. In addition, topotecan efflux was markedly enhanced in the resistant cells. To investigate the possibility that novobiocin may enhance cytotoxicity in BCRP/MXR/ABCP overexpressing cells, we exposed MCF7/TPT300 cells to novobiocin. MATERIALS AND METHODS: Cytotoxicity tests of topotecan and mitoxantrone, as well as topotecan accumulation tests, were performed with or without novobiocin in MCF7/TPT300 cells. RESULTS: Novobiocin enhances topotecan and mitoxantrone toxicity in MCF7/TPT300 cells at a clinically relevant concentration. Novobiocin enhanced cellular accumulation of topotecan and inhibited topotecan efflux in MCF7/TPT300 cells. CONCLUSION: Novobiocin may enhance topotecan and mitoxantrone toxicity in topotecan-resistant breast carcinoma cells. Novobiocin may be useful to reverse topotecan or mitoxantrone resistance in the clinic.

ATP Binding Cassette Transporter, Subfamily G, Mem↗

PubMed1998

O-glucuronidation, a newly identified metabolic pathway for topotecan and N-desmethyl topotecan.

During topotecan analysis of clinical urine samples, an additional peak eluting just after the solvent front was observed. This potential metabolite was isolated by chromatographic methods. Mass spectrometry data along with chromatographic retention data and fluorescence characteristics showed that the isolated fractions contained two compounds, i.e. topotecan-O-glucuronide and N-desmethyl topotecan-O-glucuronide. The concentrations of the metabolites in human urine were relatively low. When topotecan was given as a 30 min infusion at a dosage of 1.5 mg/m2 daily for five consecutive days every 3 weeks, the maximal metabolite concentrations in a 24 h urine sample were approximately 10% of topotecan-O-glucuronide and 3.5% of N-desmethyl topotecan-O-glucuronide with respect to the concentration of topotecan in the urine. This is the first report demonstrating that glucuronide metabolites of topotecan are present in the urine of treated patients.

Antineoplastic Agents↗

PubMed1999

Decreased topotecan platelet toxicity with successive topotecan treatment cycles in advanced ovarian cancer patients.

The dose-limiting toxicities of the DNA topoisomerase I inhibitor topotecan are hematological. We prospectively analyzed the platelet toxicity pattern in patients receiving topotecan to optimize the clinical management of topotecan hematotoxicity. Twenty-one advanced ovarian cancer patients, all pretreated with cisplatin and paclitaxel, were treated with 1.25 mg/m2/day topotecan as a 30 min infusion for 5 days, every 3 weeks. No prophylactic granulocyte colony stimulating factor (G-CSF) was given. No topotecan dose reduction was planned according to hematologic toxicity. One hundred and thirty-three topotecan courses were administered (median per patient 6; range: 1-15). Despite no dose reduction, the mean platelet nadir values were significantly less pronounced at cycle 2 than at cycle 1 (82 versus 46 x 10(3)/mm3, p=0.0007). Similar differences were found between cycle 1 and any following cycle. The percent of patients experiencing grade 4 thrombocytopenia decreased from 43% at the first cycle, to 15 and 19% at the second and third courses, respectively (p=0.058). We conclude that the currently recommended topotecan schedule is feasible in heavily pretreated ovarian cancer patients without prophylactic G-CSF. The severity of topotecan-induced thrombocytopenia is maximal at the first cycle but significantly decreases from the second cycle in the absence of dose reduction.

Adult↗

PubMedDate not supplied

[Interaction of topotecan--a DNA topoisomerase inhibitor--with dual-stranded polydeoxyribonucleotides. I. Dimerization of topotecan in solution].

Behavior of topotecan, DNA topoisomerase I inhibitor, was studied in aqueous solutions by optical methods. Topotecan absorption spectra were recorded in the pH range 0.5-11.5 and its pKa were determined. Quantum chemical calculations were made for all charge states of the topotecan molecule in lactone and carboxylate form. The calculated absorption maxima agree well with the experimental data. Protonation of the topotecan D ring (pKa = 3.6) was revealed. Comparison of experimental and calculated data showed topotecan structure with a proton at the oxygen atom at C16a rather than N4 to be the most preferable. Topotecan molecules were shown to form dimers at concentrations above 10(-5) M. Topotecan dimerization is accompanied by an increase in the pKa of hydroxy group of the A ring from 6.5 ([TPT] = 10(-6) M) to 7.1 ([TPT] = 10(-4) M), which indicates participation of this group in dimer stabilization, perhaps due to intermolecular hydrogen bonding with N1 of the B ring of a neighboring molecule. Probable dimer structures were proposed. The topotecan dimerization constant was determined, K = (4.0 +/- 0.7) x 10(3) M-1.

Dimerization↗

PubMed2004

Response to paclitaxel, topotecan, and topotecan-cyclophosphamide in children with untreated disseminated neuroblastoma treated in an upfront phase II investigational window: a pediatric oncology group study.

PURPOSE: Most children older than 1 year of age with metastatic neuroblastoma (NB) die despite intensive chemotherapy and bone marrow transplantation. The Pediatric Oncology Group conducted a study of paclitaxel, topotecan, and topotecan-cyclophosphamide (topo-cyclo) in newly diagnosed children with stage IV NB. PATIENTS AND METHODS: There were 102 patients enrolled between September 1993 and October 1995; two of them were later shown to be ineligible. Of the remaining 100 patients, the first cohort of 33 patients received paclitaxel 350 mg/m(2) intravenously (IV) over 24 hours every 14 to 21 days; the next 33 patients received topotecan 2 mg/m(2)/d for 5 days IV every 21 days; a third cohort of 34 patients were treated with IV cyclophosphamide 250 mg/m(2) followed by topotecan 0.75 mg/m(2) each day for 5 days every 21 days. Patients were re-evaluated after two courses and then treated with intensive induction therapy and bone marrow transplantation. RESULTS: Objective responses (complete response + partial response + mixed response) were documented in 67% of children who received topotecan, 76% after topo-cyclo, and 25% after paclitaxel. Four patients had grade 3 to 4 allergic reactions to paclitaxel; most patients developed grade 3 to 4 marrow suppression after topotecan or topo-cyclo. Neither disease-free survival nor overall survival differed significantly between children who received a phase II agent and those who did not. The 6-year disease-free survival and overall survival rates for all 100 children were 18% +/- 5% and 26% +/- 5%, respectively. CONCLUSION: Topotecan and topo-cyclo are active in children with NB, are well tolerated, and should be evaluated further in combination regimens.

Adolescent↗

PubMed1997

Isolation and structural confirmation of N-desmethyl topotecan, a metabolite of topotecan.

A sensitive high-performance liquid chromatography (HPLC) method for the determination of topotecan and total levels of topotecan (lactone plus its ring-opened hydroxycarboxylate form) was developed by the authors and used in several pharmacokinetics studies. During the analysis of plasma and urine samples collected in those studies, an additional peak eluting just after topotecan was observed. Approximately 100 ng of this potential metabolite was isolated from human urine using a solid-phase extraction procedure and purification by HPLC. Analysis of the isolated material by HPLC showed it to be approximately 95% pure. Mass spectrometry data along with the HPLC retention data and fluorescence data (in comparison with synthetic reference standard) are consistent with the metabolite's being N-desmethyl topotecan. The maximal concentrations of metabolite detected in human plasma and urine were relatively low. When topotecan was given as a 30-min infusion at 1.0 mg/m2 daily for 5 days every 3 weeks, the maximal plasma metabolite concentration (lactone plus the ring-opened hydroxycarboxylate form) was about 0.7% (n = 4) of the maximal total topotecan concentration. The average amount of metabolite excreted in urine during the treatment was 1-4% (n = 20) of the delivered dose.

Antineoplastic Agents↗

PubMedDate not supplied

[Interaction of topotecan--a DNA topoisomerase I inhibitor--with dual-stranded polydeoxyribonucleotides. II. Formation of a complex containing several DNA molecules in the presence of topotecan].

This study is a continuation of a series of papers dealing with topotecan interaction with double-stranded polydeoxyribonucleotides. We showed earlier that topotecan molecules form dimers in solution at concentration above 10(-5) (per base pair). Topotecan interaction with calf thymus DNA in solutions of low ionic strength was studied by fluorescence, circular dichroism, and linear flow dichroism. The data obtained indicate that topotecan forms two types of complex with DNA, DNA molecules combining with each other during formation of one of these complexes. The association constant of two topotecan-filled DNA molecules with each other was estimated at 10(4) M-1 (per base pair) in 1 mM sodium cacodylate buffer, pH 6.8, at 20 degrees C. A possibility of modulation of DNA topoisomerase I activity by topotecan due to complexation with several sites of a supercoiled DNA molecule is discussed.

Adsorption↗

PubMed1995

High-performance liquid chromatographic determination of the novel antitumour drug topotecan and topotecan as the total of the lactone plus carboxylate forms, in human plasma.

A sensitive high-performance liquid chromatographic (HPLC) assay has been developed and validated for the quantitation of the novel anticancer agent topotecan and topotecan as the total of its lactone and carboxylate forms in human plasma. Linear response in analyte standard peak area were observed over the concentration range 0.05-10 ng/ml using 100-microliters plasma samples. The instability of the drug in the biological matrix necessitated that the plasma fraction was obtained within 5 min after blood sampling by centrifugation, immediately followed by protein precipitation with cold methanol (-30 degrees C). Stability studies have indicated that topotecan is stable in these methanolic extracts for at least 4.5 months at -30 degrees C and 2 months at -70 degrees C. For the total determination of the lactone plus lactone ring-opened forms of the drug as topotecan, plasma samples were deproteinated with methanol and, subsequently, acidified with 7% (v/v) perchloric acid. Plasma samples for the measurement of total levels of the lactone and the ring-opened forms of topotecan were stable for at least 4.5 months when stored at -30 degrees C. After centrifugation, the supernatants were analysed by HPLC using a Zorbax SB-C18 Stable Bond column and methanol-0.1 M hexane-1-sulfonic acid in methanol-0.01 M N,N,N',N'-tetramethylethylenediamine (TEMED) in distilled water pH 6.0 (25:10:65, v/v) as the mobile phase. Detection was performed fluorimetrically. Within-run and between-run precision was always less than 12.1% in the concentration range of interest (0.05-10.0 ng/ml). The limit of quantitation is 0.05 ng/ml. Accuracy measurements ranged between 87.6 and 113.5%.

Antineoplastic Agents↗

PubMed2001

Glioma cell sensitivity to topotecan: the role of p53 and topotecan-induced DNA damage.

Topotecan is a topoisomerase I inhibitor which is currently evaluated as an adjuvant agent for malignant glioma. Here, we analysed the effects of topotecan on 12 human malignant glioma cell lines in vitro. All cell lines expressed topoisomerase I mRNA. High p53 protein levels, but not genetic or functional p53 status, were associated with increased topotecan-induced DNA/topoisomerase I complex formation. Neither functional p53 status, nor p53 protein levels, nor complex formation predicted topotecan-induced growth inhibition. We thus confirm a possible role for p53 protein in modulating topoisomerase I activity but conclude that the major molecular determinants of topotecan sensitivity in glioma cells await identification.

Antineoplastic Agents↗

PubMed2000

Topotecan (hycamptin) and topotecan-containing regimens in the treatment of hematologic malignancies.

Single-agent topotecan is an active drug in chemotherapy-naive MDS and CMML and, to a lesser degree, in refractory/relapsed acute leukemias, low-/intermediate-grade lymphoma, and myeloma. Its combination with cytosine arabinoside induces complete remissions in high-risk MDS/CMML. A triple-combination regimen of cyclophosphamide, cytosine arabinoside, and topotecan (CAT) was extensively tested in refractory/relapsed as well as in untreated AML. By proving effective in inducing complete remission in newly diagnosed AML at rates comparable to those achieved by anthracycline-cytosine arabinoside regimens, for example, CAT offers a useful treatment alternative. Topotecan combined with paclitaxel is promising in low-/intermediate-grade lymphomas. The activity of topotecan justifies further evaluation of topotecan-containing combination regimens, particularly in MDS/CMML and acute leukemias.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2005

Phase I trial of intravenous cisplatin-topotecan chemotherapy for three consecutive days in patients with advanced solid tumors: parallel topotecan escalation in two fixed platinum dosing schemes.

PURPOSE: We performed a phase I study of two fixed dosing schemes of cisplatin, a DNA cross-linker, with intravenous escalating topotecan, a DNA-topoisomerase I inhibitor. EXPERIMENTAL DESIGN: 40 patients with advanced solid tumors received intravenous cisplatin at a fixed dose of either 25 mg/m2 (schedule A) or 20 mg/m2 (schedule B) daily for 3 days with standard hydration. Topotecan escalation proceeded in 0.75, 0.90, 1.0, 1.15 mg/m2 cohorts in schedule A and 1.0, 1.1, 1.2, 1.3 mg/m2 cohorts in schedule B, administered intravenously at the end of cisplatin infusion daily for 3 days, repeated every 3 weeks. Dose-limiting toxicity (DLT) consisted of protracted grade IV neutropenia, febrile neutropenia, grade IV thrombocytopenia and any grade III/IV non-hematological toxicity. Epoetin and granulocyte colony-stimulating factor support was allowed on severe myeloablation. Endpoints were the identification of maximal tolerated dose (MTD), DLT and other toxicity. RESULTS: The MTD was reached in cohort 25/1.15 mg/m2 in schedule A and 20/1.2 mg/m2 in schedule B. All DLT seen consisted of three episodes of febrile neutropenia and two of grade IV thrombocytopenia in schedule A, with three episodes of febrile neutropenia and one of protracted neutropenia in schedule B. Myelosuppression was substantial in all cohorts despite granulocyte colony-stimulating factor and epoetin support, peaked on the third week of treatment and resulted in administration of chemotherapy at a median of every 4 weeks. Non-hematologic toxicity was mild. The response rate was 51% with seven complete responses occurring in patients with ovarian cancer, small cell and non-small cell lung cancer and cancer of unknown primary. The recommended dose was 20/ 1.1 mg/m2 for cisplatin and topotecan on schedule B, as the number of responses and administered topotecan dose were higher in schedule B recommended dose with lower cisplatin dose, minimizing problems of nephrotoxicity and vomiting. CONCLUSIONS: The schedule B daily cisplatin-topotecan x 3 combination with secondary cytokine support is associated with promising activity and schedule convenience. However, substantial myelosuppression undermines its applicability in the palliative setting, stressing the need for less toxic regimens.

Adolescent↗

PubMed2002

Weekly topotecan: an alternative to topotecan's standard daily x 5 schedule?

Relapsed ovarian cancer and small cell lung cancer are frequently treated with topotecan (Hycamtin), for which the standard dose and schedule are 1.5 mg/m(2) daily for five consecutive days every 3 weeks. Clinical experience has shown that this dose and schedule may be too toxic for some patients, especially those who have been heavily pretreated with platinum-based therapeutics, and it has been suggested that starting doses of topotecan be reduced to 1.0-1.25 mg/m(2)/d. Recently, multiple clinical trials have begun to evaluate the feasibility and preliminary antitumor activity of an alternative schedule based on weekly administration of topotecan. The potential benefits of weekly administration include not only reduced toxicity without significant compromise of antitumor activity, but also greater patient convenience and quality of life and greater potential for developing new topotecan-containing combination therapies. This report reviews the rationale for a weekly schedule, as well as a growing base of emerging clinical data. These preliminary data suggest that weekly topotecan is active; further evaluations are planned to confirm the activity and therapeutic index and to determine optimal dosing of a weekly schedule.

Antineoplastic Agents↗

PubMed1994

Comparative activity of oral and parenteral topotecan in murine tumor models: efficacy of oral topotecan.

Studies were performed using several tumor models to determine the oral efficacy of topotecan. These studies were direct comparisons of oral administration with parenteral treatment by the intravenous, intraperitoneal, or subcutaneous routes. Treatment schedules included bolus treatments at 4- or 7-day intervals and a split-dose regimen (q3hx4) repeated at 4- or 7-day intervals. On the various schedules, the maximally tolerated dose of topotecan was either equivalent to or at most 1.7-fold that of parenteral administration, indicative of excellent oral bioavailability in the mouse. Orally administered topotecan was comparable in efficacy to parenteral treatment in four of five tumor models tested (i.v. L1210 leukemia, i.v. B16 melanoma, i.v. and s.c. Lewis lung carcinoma). The M5076 reticulum cell sarcoma implanted i.p. responded to i.p. and s.c. but not to orally administered topotecan. These studies provide convincing support for the clinical evaluation of orally administered topotecan.

Administration, Oral↗

PubMed2005

High-performance liquid chromatographic assay for the determination of total and free topotecan in the presence and absence of anti-topotecan antibodies in mouse plasma.

A rapid and sensitive high-performance liquid chromatographic (HPLC) assay has been developed to allow determination of total (i.e. bound and unbound) and free (i.e. unbound) topotecan (TPT) in mouse plasma in the presence and absence of anti-TPT antibodies. The chromatographic analysis was carried out using reversed-phase isocratic elution with a Nova-Pak C18 column (3.9 mm x 150 mm, 4 microm) protected by a Nova-Pak C18 guard column (3.9 mm x 20 mm, 4 microm), where 10 mM KH(2)PO(4)-methanol-triethylamine (72:26:2 (v/v/v), pH 3.5) was used as the mobile phase. Topotecan was quantified with fluorescence detection using an excitation wavelength of 361 nm and an emission wavelength of 527 nm. The retention time for the internal standard, acridine, and TPT were 7.4 and 9.0 min, respectively. The lower limit of quantitation (LOQ) for TPT was determined as 0.02 ng in mouse plasma and mouse plasma ultrafiltrate, corresponding to a concentration of 1 ng/ml in 20 microl mouse plasma. The assay was shown to be linear over a concentration range of 1-500 ng/ml. The recoveries of free and total TPT from spiked mouse plasma were within 10% of theoretical values (assessed at 1, 20 and 500 ng/ml). The validated HPLC assay was applied to evaluate TPT pharmacokinetics following administration of TPT to Swiss Webster mice and to hyperimmunized and control BALB/c mice. The assay has been shown to be capable for measuring total and free TPT in mouse plasma with high sensitivity and will allow the testing of the effect of anti-TPT antibodies on the disposition of TPT.

Animals↗

PubMed2003

Determination of plasma topotecan and its metabolite N-desmethyl topotecan as both lactone and total form by reversed-phase liquid chromatography with fluorescence detection.

Topotecan (TPT) undergoes hepatic N-demethylation forming N-desmethyl topotecan (NDS). To evaluate the effect of drug-drug interactions on NDS disposition in children receiving TPT we developed and validated a sensitive and specific HPLC-fluorescence detection method for lactone and total (lactone plus carboxylate) TPT and NDS. Deproteinized plasma is vortexed, centrifuged, and the methanolic extract diluted with water for the lactone form of NDS and TPT or diluted with 1.5% phosphoric acid for NDS and TPT total. A 100 microL sample is injected onto a Varian ChromGuard RP column attached to an Agilent SB-C(18) reversed-phase analytical column held at 50 degrees C. The mobile phase (flow-rate, 0.8 mL/min) consists of methanol-aqueous buffer (27:73, v/v) (75 mM potassium phosphate and 0.2% triethylamine, pH 6.5). TPT and NDS were detected with excitation and emission wavelengths set at 376 and 530 nm, respectively. The standard curves for both forms of TPT ranged from 0.25 to 80 ng/mL, and for NDS ranged from 0.10 to 8.0 ng/mL. Within-day and between-day precision (% RSD) was </=4% for TPT and </=6.2% for NDS, respectively. Within-day and between-day percentage error ranged from 1.4 to 6.3% and from 1.4 to 2.4% for TPT, and from 1.6 to 3.1% and from 0.0 to 3.7% for NDS, respectively. No significant on-column conversion from TPT or NDS lactone to carboxylate was observed. With one method we can measure lactone and total TPT and NDS with adequate sensitivity to allow for evaluation of the disposition of these compounds in children receiving TPT.

Antineoplastic Agents↗

PubMed2006

Altered intravenous pharmacokinetics of topotecan in rats with acute renal failure (ARF) induced by uranyl nitrate: do adenosine A1 antagonists (selective/non-selective) normalize the altered topotecan kinetics in ARF?

A series of exploratory investigations with multiple agents was carried out in normal rats and in rats with uranyl nitrate-induced acute renal failure to understand the disposition characteristics of intravenous topotecan (TPT) used as a model substrate. The disposition of TPT was unaltered in normal rats when treated with methotrexate, whereas treatment with probenecid increased the systemic exposure of TPT. In case of uranyl nitrate-induced acute renal failure (UN-ARF) rats, the systemic exposure of TPT was increased when compared with normal rats, whereas in UN-ARF rats treated with probenecid a further reduction in renal clearance of TPT was noted as compared with that of UN-ARF induced rats. Thus, TPT may be involved in the tubular secretory pathway when a passive glomerular filtration pathway for elimination was not possible. The disposition of TPT did not normalize in UN-ARF rats when treated with caffeine, a non-selective adenosine A1 receptor antagonist, whereas the selective adenosine A1 receptor antagonist (1,3-dipropyl-8-phenylxanthine, DPPX) normalized TPT pharmacokinetic disposition by improving renal function. Renal excretion studies demonstrated that CLR improved by almost fivefold following DPPX treatment in ARF rats. In addition, the qualitative stability/metabolism pattern of TPT in liver microsomes prepared from various groups of rats (normal rats, UN-ARF rats, rats treated with DPPX, and UN-ARF rats treated with DPPX) was found to be similar. In summary, using a pharmacokinetic tool as a surrogate, it has been shown that the pharmacokinetic disposition of TPT improved considerably upon treatment with DPPX, a selective adenosine A1 antagonist.

Acute Kidney Injury↗

PubMed2006

Using plasma topotecan pharmacokinetics to estimate topotecan exposure in cerebrospinal fluid of children with medulloblastoma.

The purpose of this study was to estimate ventricular cerebrospinal fluid (vCSF) topotecan lactone (TPT) exposures in pediatric medulloblastoma patients from plasma concentration-time data by using a pharmacokinetic (PK) model. We studied children with high-risk medulloblastoma who received pharmacokinetically guided TPT (target plasma area under the concentration-time curve [AUC], 120-160 ng/ml-h) and obtained serial vCSF samples to assess TPT exposure. Population pharmacokinetic parameters were determined by using linear mixed-effects modeling via the two-stage approach. We simulated TPT vCSF exposure duration at plasma TPT AUC values of 120 to 200 ng/ml-h and determined percentages of studies meeting or exceeding the vCSF exposure duration threshold (EDT) of 1 ng/ml for 8 h. We then used bootstrap methods to estimate variability in vCSF EDT. Eighteen PK studies were conducted in six patients (median age, 4.8 years). In these patients, seven of nine studies attaining target plasma TPT AUC achieved the vCSF EDT. Given a plasma TPT AUC of 120 ng/ml-h, the median percentage of results meeting or exceeding EDT was 78% (95% CI, 61%-100%). One patient (four studies) with tumor blockage of CSF flow, which can alter CSF pharmacokinetics, was removed, and the bootstrap analysis was repeated. In this subset, a median 93% (95% CI, 79%-100%) of studies achieved vCSF EDT. Increasing plasma TPT AUC values resulted in increased ability to achieve vCSF EDT. We demonstrated that a plasma PK model could estimate vCSF TPT concentrations. Further, our results indicate that the TPT vCSF EDT can be achieved in more than 80% of studies targeted to a plasma TPT AUC of 120 ng/ml-h.

Adolescent↗