The use of Ctrough for the therapeutic drug monitoring of olaparib in patients with ovarian cancer.

OBJECTIVE: Olaparib is the poly-[Adenosine diphosphate ribose (ADP-ribose)] polymerase inhibitor (PARPI) used in maintenance therapy of patients with platinum-sensitive ovarian cancer with mutations in breast cancer genes 1/2 (BRCA1/2). Oncologists still do not have recommendations of treatment depending on efficient plasma concentrations of the PARP inhibitor. The aim of the study was the assessment of plasma trough concentrations of olaparib at steady state (Ctrough) in ovarian cancer patients. The severity of olaparib adverse effects (AEs) was noted. PATIENTS AND METHODS: The retrospective study involved 33 patients [mean standard deviation (SD)]; age 57.0 (8.4) years; weight 68.7 (13.7) kg; and body mass index (BMI) 26.4 (4.9) kg/m2, with ovarian cancer treated with olaparib (tablets in dose 300 mg/12 h, 250 mg/12 h, 200 mg/12 h or capsules 400 mg/12 h, 200 mg/12 h, 100 mg/12 h). Plasma drug levels were measured by HPLC-UV method (λ = 254 nm; Symmetry C8 column; gradient flow). The severity of olaparib AEs was assessed by Common Terminology Criteria for Adverse Events (CTCAE) v5.0 scale. Drug interactions were analyzed. RESULTS: In total, 130 measurements (n) of Ctrough were determined in 33 patients (median sample frequency per patient was 4). The olaparib Ctrough in patients with AEs was 87.840-7,213.262 ng/mL [coefficient of variation (CV) = 91%], in patients without AEs 48.021-7,073.350 ng/mL (CV = 88%). AEs were the following: fatigue (modest, n = 4, severe, n = 2), anemia (grade G1 n = 66, G2 n = 6, G3 n = 3), neutropenia (grade G1 n = 15, G2 n = 4), prediabetes (n = 1). There was a correlation between Ctrough and olaparib-induced fatigue (p = 0.0015). The lower values of dose-adjusted olaparib concentrations (p = 0.0121) and dose/kg-adjusted olaparib concentrations (p = 0.0389) were correlated with higher grade of neutropenia. CONCLUSIONS: There was a correlation between Ctrough, expressed as ng/ml, ng/ml/mg or ng/ml/mg/kg, and fatigue degree, but not anemia. Patients with neutropenia had statistically significant lower plasma concentrations of olaparib.

Model molecules for the active centre of alcoholdehydrogenases--an FT-IR study.

We synthesized a triamide of Kemp's acid with two cysteine groups and one histidine group (compound 1), and a triamide of 1,3,5-pentane tricarboxylic acid with tyrosine, histidine, and arginine molecules (compound 2). From compound 1 we obtained the hydrated Zn2+ complex, compound 3. The FT-IR spectra of various complexes of compounds 1-3 with NAD+ show no IR continua and hence, no hydrogen-bonded chains with proton polarizability are present. In the case of the complex (compounds 2 and 3 and NAD+) an intense continuum demonstrates that a hydrogen-bonded chain is formed with large proton polarizability due to collective proton motion. This proton pathway is discussed. The O atom of the nicotinamide group of NAD+ is a strong hydrogen bond acceptor. This result is discussed with regard to the catalytic mechanism.

A model molecule of the hydrogen-bonded chain in the active site of bacteriorhodopsin.

We synthesized a 2-N-methylaminoethyl-tetramethylquanidine amide of Kemp's triacid (CP2). Furthermore, we added to CP2 tetrabutylammonium 4-tert-butylphenolate. The pKa value of 4-tert-butylphenol is comparable to that of tyrosine. We studied by FT-IR spectroscopy CP2 and the complex of CP2 with 4-tert-butylphenolate. This complex is a model for the hydrogen-bonded chain in the active centre of the bacteriorhodopsin molecule. An intense continuum in the FT-IR spectra demonstrates that this hydrogen-bonded chain shows large proton polarizability due to collective proton motion. As earlier demonstrated also Schiff base carboxylic acid bonds show large proton polarizability. Thus, in all these hydrogen bonds protons can easily be shifted by collective proton motion due to changes of the local electrical fields and by changes of specific interactions arising from conformational changes.