Pharmacokinetic evaluation of gemcitabine and 2′,2′-difluorodeoxycytidine-5′-triphosphate after prolonged infusion in patients affected by different solid tumors

Cattel, Luigi; Airoldi, Mario; Delprino, Laura; Passera, Roberto; Milla, Paola; Pedani, Fulvia

doi:10.1093/annonc/mdj970

Cited by 35 publications

(31 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The 75-mg BID dose has not been tested in monotherapy studies and, therefore, no comparison of pharmacokinetic parameters and trough concentrations can be made. Although mean gemcitabine concentrations on week 2 were slightly higher than those on week 1, exposure to gemcitabine, both alone and in combination with motesanib, was no greater than the exposure observed in previous studies investigating gemcitabine monotherapy (Cattel et al, 2006;Gietema et al, 2006).…”

Section: Discussioncontrasting

confidence: 66%

Safety and pharmacokinetics of motesanib in combination with gemcitabine for the treatment of patients with solid tumours

et al. 2008

View full text Add to dashboard Cite

The aim of this open-label phase 1b study was to assess the safety and pharmacokinetics of motesanib in combination with gemcitabine in patients with advanced solid tumours. Eligible patients with histologically or cytologically documented solid tumours or lymphoma were enroled in three sequential, dose-escalating cohorts to receive motesanib 50 mg once daily (QD), 75 mg two times daily (BID), or 125 mg QD in combination with gemcitabine (1000 mg m À2 ). The primary end point was the incidence of doselimiting toxicities (DLTs). Twenty-six patients were enroled and received motesanib and gemcitabine. No DLTs occurred. The 75 mg BID cohort was discontinued early; therefore, 125 mg QD was the maximum target dose. Sixteen patients (62%) experienced motesanib-related adverse events, most commonly lethargy (n ¼ 6), diarrhoea (n ¼ 4), fatigue (n ¼ 3), headache (n ¼ 3), and nausea (n ¼ 3). The pharmacokinetics of motesanib and of gemcitabine were not markedly affected after combination therapy. The objective response rate was 4% (1 of 26), and 27% (7 of 26) of patients achieved stable disease. In conclusion, treatment with motesanib plus gemcitabine was well tolerated, with adverse event and pharmacokinetic profiles similar to that observed in monotherapy studies.

show abstract

Section: Discussioncontrasting

confidence: 66%

Safety and pharmacokinetics of motesanib in combination with gemcitabine for the treatment of patients with solid tumours

et al. 2008

View full text Add to dashboard Cite

show abstract

“…40,41 Similarly, plasma concentrations of 2.5-20 mM are achievable during treatment with gemcitabine. 42 The AZT susceptibility observed in this study clearly relates to TK activity and apparently the KY895 strain is a good model to study AZT activation (Figure 2a). Non-TK1-like dNKs did not render the KY895 susceptible to AZT (Table 2).…”

mentioning

confidence: 68%

Nucleoside analogues are activated by bacterial deoxyribonucleoside kinases in a species-specific manner

Sandrini

Clausen

et al. 2007

Journal of Antimicrobial Chemotherapy

View full text Add to dashboard Cite

Objectives: To investigate the bactericidal activity of antiviral and anticancer nucleoside analogues against a variety of pathogenic bacteria and characterize the activating enzymes, deoxyribonucleoside kinases (dNKs).Methods: Several FDA-approved nucleoside analogue drugs were screened for their potential bactericidal activity against several clinical bacterial isolates and type strains. We identified and subcloned the genes coding for putative deoxyribonucleoside kinases in Escherichia coli, Pasteurella multocida, Salmonella enterica, Yersinia enterocolitica, Bacillus cereus, Clostridium perfringens and Listeria monocytogenes. These genes were tested for their ability to increase the susceptibility of a dNK-deficient E. coli strain to various analogues. We overexpressed, purified and characterized the substrate specificity and kinetic properties of the recombinant enzymes from S. enterica and B. cereus.Results: The tested Gram-negative bacteria were susceptible to 3 0 -azido-3 0 -deoxythymidine (AZT) in the concentration range 0.032 -31.6 mM except for a single E. coli isolate and two Pseudomonas aeruginosa isolates which were resistant to the tested AZT concentrations. Purified recombinant S. enterica thymidine kinase phosphorylated AZT efficiently with a K m of 73.3 mM and k cat /K m of 6.6 3 10 4 s 21 M 21 and is the activator of this drug in vivo. 2 0 ,2 0 -Difluoro-2 0 -deoxycytidine (gemcitabine) was a potent antibiotic against Gram-positive bacteria in the concentration range between 0.001 and 1.0 mM. The B. cereus deoxyadenosine kinase had a K m for gemcitabine of 33.5 mM and k cat /K m of 5.1 3 10 3 s 21 M 21 and activates gemcitabine in vivo. S. enterica and B. cereus are now amongst the first bacteria with a completely characterized set of dNK enzymes.Conclusions: Bacterial dNKs efficiently activate nucleoside analogues in a species-specific manner. Therefore, nucleoside analogues have a potential to be employed as antibiotics in the fight against emerging multiresistant bacteria.

show abstract

“…For the 5-FU nucleotides, the development of an appropriate assay proved even more difficult than for other nucleotide analogs because intracellular 5-FU nucleotide concentrations, especially those following capecitabine treatment, are much lower [17,18]. Maximization of the release from the cell matrix and minimization of endogenous interference were therefore critical factors in obtaining an appropriate assay.…”

Section: Introductionmentioning

confidence: 99%

Development of an LC–MS/MS assay for the quantitative determination of the intracellular 5-fluorouracil nucleotides responsible for the anticancer effect of 5-fluorouracil

Derissen

Hillebrand

Rosing

et al. 2015

Journal of Pharmaceutical and Biomedical Analysis

View full text Add to dashboard Cite

Pharmacokinetic evaluation of gemcitabine and 2′,2′-difluorodeoxycytidine-5′-triphosphate after prolonged infusion in patients affected by different solid tumors

Cited by 35 publications

References 19 publications

Safety and pharmacokinetics of motesanib in combination with gemcitabine for the treatment of patients with solid tumours

Safety and pharmacokinetics of motesanib in combination with gemcitabine for the treatment of patients with solid tumours

Nucleoside analogues are activated by bacterial deoxyribonucleoside kinases in a species-specific manner

Development of an LC–MS/MS assay for the quantitative determination of the intracellular 5-fluorouracil nucleotides responsible for the anticancer effect of 5-fluorouracil

Contact Info

Product

Resources

About