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  • ISSN: 2333-7079
    Pharmacokinetics and Pharmacodynamics
    Special Issue on Pharmacokinetics and Pharmacodynamics
    Minjie Wei
    China Medical University
    No.92, Bei'er Road, Heping District
    Shenyang, 110001, China
    Research Article
    Jennifer Le1,2*, Florin Vaida1, Emily Nguyen2, Felice C. Adler-Shohet3, Gale Romanowski1, Jiah Kim1, Tiana Vo2, and Edmund V. Capparelli1
    Background: Vancomycin dosing to achieve the area-under-the-curve to minimum inhibitory concentration (AUC/MIC) target of ≥ 400 in children with renal insufficiency is unknown. Our objectives were to compare vancomycin clearance (CL) and initial dosing in children with normal and impaired renal function.
    Methods: Using a matched case-control study in subjects ≥ 3 months old who received vancomycin ≥ 48 hr, we performed population-based modeling with empiric Bayesian post-hoc individual parameter estimations and Monte Carlo simulations. Cases, defined by baseline serum creatinine (SCr) ≥ 0.9 mg/dL, were matched 1:1 to controls by age and weight.
    Results: Analysis included 63 matched pairs with 319 serum concentrations. Mean age (± SD) was 13 ± 6 yr and weight, 51 ± 25 kg. Mean baseline SCr was 0.6 ± 0.2 mg/dL for controls, and 1.3 ± 0.5 for cases. Age, SCr, and weight were independent covariates for CL. Final model parameters and inter-subject variability (ISV) were: CL(L/hr) = 0.235*Weight0.75*(0.64/SCr)0.497*(ln(DOL)/8.6)1.19 ISV=39%, where DOL is day of life. Target AUC/MIC ≥ 400 was achieved in 80% of cases at vancomycin 45 mg/kg/day, but required 60 mg/kg/day for controls. Drug CL improved in 87% of cases due to recovery of renal function.
    Conclusion: Due to reduced drug CL, a less frequent dosing at 15 mg/kg every 8 hr (i.e., 45 mg/kg/day) is appropriate for children with renal impairment. Close monitoring of renal function and drug concentrations is prudent to ensure adequate drug exposure, especially in those with renal impairment since recovery of renal function may occur during therapy.
    Yi-Lin Chiu*, Martin S King, Cheri E Klein, Daniel Cohen, and Barry Bernstein
    Background: Therapeutic drug monitoring (TDM) guidance suggests that lopinavir trough concentration < 1 or < 3 mcg/mL may be associated with virologic failure. The aim of this analysis was to evaluate the association between lopinavir exposure and virologic response in antiretroviral-naïve subjects.
    Methods: Data from previously antiretroviral-naïve subjects enrolled in 5 clinical trials of lopinavir/ritonavir (administered BID or QD) plus 2 NRTIs were utilized. Plasma HIV-1 RNA and lopinavir trough concentrations were collected simultaneously at multiple post-baseline visits. Lopinavir exposure and virologic response relationship were analyzed.
    Results: At Week 48, the suppression rates were similar between subjects with concentration below or above TDM cutoff values. Similar results were obtained when subjects who received lopinavir/ritonavir QD were evaluated separately. In the exposure-response models, there was no significant association between lopinavir trough concentration and virologic response.
    Conclusions: Trough lopinavir concentrations did not predict the virologic outcome in 856 antiretroviral-naïve subjects treated with lopinavir/ritonavir plus 2 NRTIs. No threshold value for trough lopinavir concentration which resulted in a suboptimal response was identified raising question as to the clinical utility of therapeutic drug monitoring to assess virologic response to lopinavir/ritonavir based therapy in patients on an initial antiretroviral drug regimen.
    Sam Holford1, Karel Allegaert2, Brian J. Anderson3, Butch Kukanich4, Altamir B. Sousa5, Amir Steinman6, Bruno Pypendop7, Reza Mehvar8, Mario Giorgi9 and Nick Holford1*
    Abstract: Allometric principles were used to discern cross-species differences in tramadol disposition and formation of its primary analgesic metabolite, (+)-O-desmethyl-tramadol (M1). Species differences in formation of M1 may help predict the analgesic effectiveness of tramadol. Tramadol was administered intravenously by a zero-order (constant infusion) process or rapid bolus dose and racemic concentrations of tramadol and M1 measured. Data were pooled to define differences between species (human, rat, cat, dog, goat, donkey and horse). A two-compartment linear disposition model with first-order elimination was used to describe tramadol and M1 disposition. Slow metabolizers were detected in 6% of the population and tramadol clearance to M1 was 16.2% that of extensive metabolizers. Tramadol clearance to M1 was slower and tramadol clearance by other pathways was faster in rats, dogs, and horses compared to humans. There are substantial differences between species in the pharmacokinetics of tramadol and its M1 metabolite, which are not explained by differences in body weight. The hypothesis that volumes of distribution are similar across species was shown not to be true. M1 exposure in the goat, donkey and cat was comparable to humans, which indicates it is likely to be an effective analgesic at typically used doses in these species but not in dogs or horses.
    Parul Gupta1 and Pratima Srivastava2*
    Abstract: Trioxanes are the new antimalarial series of potent compound having the capability to harness the over growing menace of malaria and its acquisition of resistance. In this manuscript the authors have presented results of the metabolic studies of a potent trioxane series of antimalarial compound, CDRI-97/78, developed at Central Drug Research Institute. About 75% of the CDRI-97/78 was metabolised to CDRI-97/63. Further metabolites of CDRI-97/63 were not noticed. The metabolism of CDRI compound 97/78 and 97/63 was mainly in the microsomal fraction only a small fraction can be attributed towards the cytosolic fraction, thus reflecting the prominence of Phase 1 reactions during metabolism. The metabolic reaction as depicted by the kinetic parameters show that the clearance of CDRI- 97/78 is about twice more in S9 fraction as compared to the microsomal fraction. Thus pointing towards further metabolism of the CDRI- 97/63, also the nonsignificant change observed in case of the Vmax and velocity in S9 and microsomal fraction depict the that majorily one isoform of cytochrome P-450 is involved in the metabolism of CDRI-97/78. Ketoconazole (CYP3A2 inhibitor) and Aminobenzotriazole completely inhibited the rate of reaction depicting the involvement of Phase 1 reactions particularly CYTOCHROME P450 3A2 isoform; whereas, verapamil (CYP2E1); cimetidine (CYP1A2); omeprazole (CYP2C19); quinidine (CYP2D6); sulphaphenazole and isoniazid (CYP2C9) did not affected the rate of reaction.
    Aulma R Parker1, Vicki L Nienaber2, Pavankumar N Petluru1, Vandana Sridhar2, Betsy D Leverett1, Philippe Y Ayala1, Min Zhao1, Barbara Chie-Leon2, Kamwing Jair1, Harry Kochat1, John Badger2 and Frederick H Hausheer1*
    Abstract: We investigated the interactions between Thioredoxin (Trx) and BNP7787 (Tavocept®). BNP7787 is a water-soluble disulfide that appears well-tolerated and nontoxic, and in separate randomized multicenter Phase 2 and Phase 3 clinical trials in NSCLC patients, BNP7787 in combination with standard chemotherapy, resulted in substantial increases in the overall survival of patients with advanced adenocarcinoma sub-type NSCLC.
    Activity assays indicate that BNP7787 and BNP7787-derived mesna disulfide heteroconjugates are novel alternative substrates of Trx with the potential to inhibit turnover of endogenous Trx substrates. LC-MS studies indicate that BNP7787 forms a covalent mixed-disulfide with Trx on cysteine residues 62, 69 and 73. BNP7787-modified Trx is less active than apo-Trx. X-ray crystallographic studies unequivocally confirm that BNP7787 forms stable mixed disulfides with Trx. BNP7787-modified Trx crystallized as a disulfide-linked tetramer with novel interactions between BNP7787-derived mesna and Trx, including stable BNP7787-derived mixed mesna-cysteine disulfides on human Trx resulting in unique, previously unidentified Trx structural conformations. Molecules A and B of the tetramer are identical to each other and exist in a conformation similar to other published Trx crystals. Molecules C and D, also identical to each other, undergo a significant conformational change relative to molecules A and B, and exhibit substantial disulfide reshuffling.
    Inhibition or modulation of Trx by BNP7787 through covalent or non-covalent means may have important ramifications in cancers with elevated Trx activity, including adenocarcinoma sub-type NSCLC, and could impact Trx-related signaling pathways important for the inhibition of apoptosis and cell proliferation.
    Research Article
    BerlindaJ. de Wit – van der Veen*, Marcel P.M. Stokkel
    Advances in the oncological sciences have led to the development of agents that are designed to affect specific molecular pathways. However, many of these immunotherapeutic agents do not successfully pass phase 2 trials due to concerns with efficacy, toxicity or side effects. The generalized endpoints that traditionally have been used in these trials, such as maximum tolerated dose and overall response, may be less optimal for immunotherapeutic agents. The addition of in vivo nuclear imaging in these early trials can aid in patient stratification, evaluation of drug bio distribution, pharmacodynamic effects and tumor heterogeneity. This review discusses the advantages of nuclear imaging, and outlines the first application of these imaging biomarkers in clinical trials.
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