Pharmacokinetics, bioavailability and effects on electrocardiographic parameters of oral fludarabine phosphate.

The pharmacokinetics, bioavailability and effects on electrocardiographic (ECG) parameters of fludarabine phosphate (2F-ara-AMP) were evaluated in adult patients with B-cell chronic lymphocytic leukemia. Patients received single doses of intravenous (IV) (25 mg/m(2), n=14) or oral (40 mg/m(2), n=42) 2F-ara-AMP. Plasma concentrations of drug and metabolites and digital 12-lead ECGs were monitored for 23 h after dosing. The dephosphorylated product fludarabine (2F-ara-A) was the principal metabolite present in the systemic circulation. Mean (+/-SD) elimination half-life did not differ significantly between IV and oral dosage groups (11.3+/-4.0 vs 9.7+/-2.0 h, p=0.053). Renal excretion was a major clearance pathway, along with transformation to a hypoxanthine metabolite 2F-ara-Hx. Estimated mean oral bioavailability of 2F-ara-A was 58%. Compared to the time-matched drug-free baseline Fridericia correction of the QT interval (QTcF), the mean QTcF change following 2F-ara-AMP did not differ from zero, and a treatment effect of >+10 and >+15 ms could be excluded following oral and IV 2F-ara-AMP, respectively. Similarly, heart rate, PR interval and QRS duration did not change following 2F-ara-AMP treatment. Thus the 25 mg/m(2) IV and 40 mg/m(2) oral doses of 2F-ara-AMP produce similar systemic exposure, and do not prolong QTcF, indicating low risk of drug induced Torsades de Pointes.

Targeted radiopharmaceutical therapy for advanced lung cancer: phase I trial of rhenium Re188 P2045, a somatostatin analog.

BACKGROUND: Both small cell and non-small cell lung cancer overexpress somatostatin receptors (SSTR). P2045 peptide is an 11-amino acid somatostatin analog that binds with high affinity to SSTR and can be labeled with Tc-99m to gauge receptor prevalence or with Re-188 for 2.1 MeV beta radiotherapy. To evaluate the safety of this approach, a phase I dose-escalation study of Re-188 P2045 in SSTR-positive lung cancer was performed. METHODS: Patients were required to have stage IIIb or IV or recurrent non-small cell lung cancer or extensive stage or recurrent small cell lung cancer, performance status 0 to 1, and normal organ function. There were no limitations on the number of prior therapies. Tumor SSTR was detected with Tc-99m P2045. If positive and projected renal dose of radiation from Re-188 P2045 was less than 20 Gy, treatment with escalating doses of Re-188 P2045 was instituted. Three doses were evaluated 30 mCi/m2, 60 mCi/m2, and 90 mCi/m2. A single dose of Re-188 P2045 was allowed. Dose-limiting toxicity was defined as > or = grade 3 nonhematologic toxicity or grade 4 hematologic toxicity. RESULTS: Fifteen patients were enrolled. The median age was 61 years. Fourteen patients had > or = 2 prior chemotherapy regimens. All were imaged with Tc-99m P2045, eight patients received Re-188 P2045. The most common toxicity was mild lymphopenia. The trial was halted at the 90 mCi/m2 level when three patients were projected to have renal radiation doses above 20 Gy. The monoclonal antibody was not determined, and no responses were seen. Five of the eight patients (62.5%, 95% CI: 24-91%) had stable disease for at least 8 weeks, all of whom entered the study with progressive disease. Median overall survival was 11.5 months. CONCLUSIONS: This trial demonstrated that Re-188 P2045 was well tolerated. Tc-99m P2045 imaging allows identification of patients who may benefit from this treatment. Although responses were not seen, survival for these heavily pretreated patients is interesting and merits further research.

Somatostatin receptor-binding peptides suitable for tumor radiotherapy with Re-188 or Re-186. Chemistry and initial biological studies.

Somatostatin derivative peptides previously designed for radiodiagnostic purposes (99mTc P829 or 99mTc depreotide) were reoptimized for radiotherapy of tumors with rhenium radioisotopes. An optimized pharmacophore peptide P1839 was derived by in vitro binding affinity assay to AR42J rat pancreatic tumor cell membranes. Peptides with chelating domains and their oxorhenium(V) complexes were tested in vitro for binding to NCI H69 human SCLC tumor membranes. Further optimization entailed radiolabeling with 99mTc and biodistribution in an AR42J xenograft mouse model. Kidney uptake was decreased substantially by removing positively charged residues. Neutral N3S diamide amine thiol chelators with no adjacent positive charges had the best overall properties. Substituting an aromatic amino acid into the chelator approximately doubled the tumor uptake. The final optimized peptide P2045 (39) radiolabeled with 99mTc exhibited increased tumor uptake ( approximately 25 %ID/g at 1.5 h), lower kidney uptake ( approximately 4.8 %ID/g at 1.5 h), and extensive urinary excretion (59 %ID at 1.5 h). Finally, comparison biodistribution studies between 99mTc and 188Re (39) showed a good correlation between the two metal complexes and demonstrated prolonged tumor retention (> or =24 h).