Publications by authors named "Nuggehally R Srinivas"

261 Publications

Whole blood or plasma: what is the ideal matrix for pharmacokinetic-driven drug candidate selection?

Future Med Chem 2021 Jan 4;13(2):157-171. Epub 2020 Dec 4.

Kenox Pharmaceuticals Inc., Monmouth Junction, NJ 08852, USA.

In the present era of drug development, quantification of drug concentrations following pharmacokinetic studies has preferentially been performed using plasma as a matrix rather than whole blood. However, it is critical to realize the difference between measuring drug concentrations in blood versus plasma and the consequences thereof. Pharmacokinetics using plasma data may be misleading if concentrations differ between plasma and red blood cells (RBCs) because of differential binding in blood. In this review, factors modulating the partitioning of drugs into RBCs are discussed and the importance of determining RBC uptake of drugs for drug candidate selection is explored. In summary, the choice of matrix (plasma vs whole blood) is an important consideration to be factored in during drug discovery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4155/fmc-2020-0187DOI Listing
January 2021

A concise review of bioanalytical methods of small molecule immuno-oncology drugs in cancer therapy.

Biomed Chromatogr 2021 Jan 24;35(1):e4996. Epub 2020 Nov 24.

Jubilant Biosys, Bangalore, India.

Immuno-oncology (IO) is an emerging option to treat cancer malignancies. In the last two years, IO has accounted for more than 90% of the new active drugs in various therapeutic indications of oncology drug development. Bioanalytical methods used for the quantitation of various IO small molecule drugs have been summarized in this review. The most commonly used are HPLC and LC-MS/MS methods. Determination of IO drugs from biological matrices involves drug extraction from the biological matrix, which is mostly achieved by simple protein precipitation, liquid-liquid extraction and solid-phase extraction. Subsequently, quantitation is usually achieved by LC-MS/MS, but HPLC-UV has also been employed. The bioanalytical methods reported for each drug are briefly discussed and tabulated for easy access. Our review indicates that LC-MS/MS is a versatile and reliable tool for the sensitive, rapid and robust quantitation of IO drugs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/bmc.4996DOI Listing
January 2021

Enantioselective in vitro ADME, absolute oral bioavailability, and pharmacokinetics of (-)-lumefantrine and (+)-lumefantrine in mice.

Xenobiotica 2021 Feb 23;51(2):202-209. Epub 2020 Sep 23.

Drug Metabolism and Pharmacokinetics, Jubilant Biosys, Industrial Suburb, Bangalore, India.

Lumefantrine (LFN) is a chiral antimalarial drug. Enantioselective attributes and absolute oral pharmacokinetics for (-)-LFN and (+)-LFN have been characterized in mice. No stereoselectivity was seen with either of the enantiomers when compared with -LFN in the executed studies (solubility, metabolic stability, protein binding, permeability and blood partitioning). Post intravenous or oral administration of -LFN, the AUC and MRT of (+)-LFN was higher over (-)-LFN, which is reflected in higher clearance value for (-)-LFN. Following (-)-LFN intravenous administration to mice, the key PK parameters were comparable to (-)-LFN from -LFN; however, post intravenous administration of (+)-LFN alone to mice, the AUC was 1.3-fold higher than (+)-LFN from -LFN. Similarly, post oral administration of (-)-LFN to mice, both AUC and C were 1.3-fold higher than (-)-LFN from -LFN. On other hand, (+)-LFN showed 1.4-fold higher AUC and 1.7-fold higher C post oral administration over (+)-LFN from -LFN.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/00498254.2020.1823523DOI Listing
February 2021

ZYBT1, a potent, irreversible Bruton's Tyrosine Kinase (BTK) inhibitor that inhibits the C481S BTK with profound efficacy against arthritis and cancer.

Pharmacol Res Perspect 2020 08;8(4):e00565

Department of Medicinal Chemistry, Zydus Research Center, Ahmedabad, Gujarat, India.

Bruton's tyrosine kinase (BTK) plays a central and pivotal role in controlling the pathways involved in the pathobiology of cancer, rheumatoid arthritis (RA), and other autoimmune disorders. ZYBT1 is a potent, irreversible, specific BTK inhibitor that inhibits the ibrutinib-resistant C481S BTK with nanomolar potency. ZYBT1 is found to be a promising molecule to treat both cancer and RA. In the present report we profiled the molecule for in-vitro, in-vivo activity, and pharmacokinetic properties. ZYBT1 inhibits BTK and C481S BTK with an IC of 1 nmol/L and 14 nmol/L, respectively, inhibits the growth of various leukemic cell lines with IC of 1 nmol/L to 15 μmol/L, blocks the phosphorylation of BTK and PLCγ2, and inhibits secretion of TNF-α, IL-8 and IL-6. It has favorable pharmacokinetic properties suitable for using as an oral anti-cancer and anti-arthritic drug. In accordance with the in-vitro properties, it demonstrated robust efficacy in murine models of collagen-induced arthritis (CIA) and streptococcal cell wall (SCW) induced arthritis. In both models, ZYBT1 alone could suppress the progression of the diseases. It also reduced the growth of TMD8 xenograft tumor. The results suggested that ZYBT1 has high potential for treating RA, and cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/prp2.565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7424564PMC
August 2020

Simultaneous determination of colchicine and febuxostat in rat plasma: Application in a rat pharmacokinetic study.

Biomed Chromatogr 2020 Nov 24;34(11):e4939. Epub 2020 Jul 24.

Drug Metabolism and Pharmacokinetics, Jubilant Biosys Ltd, Bangalore, India.

A selective, sensitive and rapid LC-MS/MS method has been developed and validated as per US Food and Drug Administration regulatory guidelines for the simultaneous quantitation of colchicine and febuxostat in rat plasma. Colchicine and febuxostat were extracted from the rat plasma using 10% tert-butyl methyl ether in ethyl acetate using colchicine-d as an internal standard (IS). The chromatographic separation of colchicine, febuxostat and the IS was achieved using a mobile phase comprising 5 mm ammonium formate and 0.025% formic acid in acetonitrile (20:80, v/v) in isocratic mode on an Eclipse XDB-C column. The injection volume and flow rate were 5.0 μl and 0.9 ml/min, respectively. Colchicine and febuxostat were detected by positive electrospray ionization in multiple reaction monitoring mode using transition pairs (Q1 → Q3) of m/z 400.10 → 358.10 and 317.05 → 261.00, respectively. The assay was linear in the ranges of 0.25-254 and 2.60-622 ng/ml for colchicine and febuxostat, respectively. The inter- and intra-day precision values were 0.58-13.0 and 1.03-4.88% for colchicine and febuxostat, respectively. No matrix or carryover effects were observed during the validation. Both analytes were stable on the bench-top, in the autosampler and in storage (freeze-thaw cycles and long-term storage at -80°C). A pharmacokinetic study in rats was performed to show the applicability of the validated method.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/bmc.4939DOI Listing
November 2020

Novel methodology to perform incurred sample reanalysis on dried blood spot cards: Experimental data using darolutamide and filgotinib.

Biomed Chromatogr 2020 Nov 23;34(11):e4938. Epub 2020 Jul 23.

Drug Metabolism and Pharmacokinetics, Jubilant Biosys, Industrial Suburb, Yeshwanthpur, Bangalore, Karnataka, India.

Different options on performing incurred sample reanalysis (ISR) on dried blood spot (DBS) cards were investigated using drugs belonging to various therapeutic areas: (a) darolutamide (to treat prostate cancer) and (b) filgotinib (to treat rheumatoid arthritis). The proposed novel methodology included the generation of half-DBS and quarter-DBS discs after initial blood collection using the full-DBS discs. Accordingly, blood collection via DBS was performed in male BALB/c mice following intravenous and oral dosing of darolutamide; in male Sprague Dawley rats following intravenous and oral dosing of filgotinib. The ISR data generated from the full-DBS disc, half-DBS disc and quarter-DBS disc were compared for the assessment of the proposed methodology. Quantification of darolutamide and filgotinib was accomplished using liquid chromatography-electrospray ionization/tandem mass spectrometry methods. Darolutamide and filgotinib ISR samples, which were collected and prepared using full-, half- and quarter-DBS discs, met the acceptance criteria for ISR analysis. In conclusion, this is the first report showing a viable tool for the performance of ISR on DBS cards. The use of quarter- or half-DBS discs would aid in not only ISR but also in long-term storage experiments of analytes because it would avoid the need for additional blood sampling in patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/bmc.4938DOI Listing
November 2020

Pharmacokinetics of Darolutamide in Mouse - Assessment of the Disposition of the Diastereomers, Key Active Metabolite and Interconversion Phenomenon: Implications to Cancer Patients.

Drug Metab Lett 2020 May 20. Epub 2020 May 20.

Drug Metabolism and Pharmacokinetics, Yeshwanthpur, Bangalore-560 022. India.

Background: Darolutamide is recently approved for the treatment of non-metastatic castrate resistance prostate cancer. Hitherto, no stereoselective pharmacokinetic data has been published pertaining to darolutamide and its diastereomers in animals or humans. The key aims of the experiment were to examine darolutamide, S,S-darolutamide and S,R-darolutamide with respect to (a) assessment of in vitro stability and protein binding (b) characterization of in vivo oral and intravenous pharmacokinetics in mice.

Method: In vitro (liver microsomes stability and protein binding) and in vivo experiments (oral/intravenous dosing to mice) were carried out using darolutamide, S,S-darolutamide and S,R-darolutamide. Besides, tissue levels of darolutamide, S,S-darolutamide and S,R-darolutamide were measured following oral and intravenous dosing. Appropriate plasma/tissue samples served to determine the pharmacokinetics of various analytes in mice. Liquid chromatography in tandem with mass spectrometry procedures enabled the delineation of the plasma pharmacokinetics, in vitro and tissue uptake data of the various analytes.

Results: Chiral inversion was absent in the metabolic stability study. However, darolutamide showed profound stereoselectivity (S,Sdarolutamide greater than S,R-darolutamide) after either intravenous or oral dosing. S,R-darolutamide but not S,S-darolutamide showed conversion to its antipode post oral and intravenous dosing to mice. Regardless of oral or intravenous dosing, active keto darolutamide formation was evident after administration of darolutamide, S,S-darolutamide or S,R- darolutamide. Tissue data supported the observations in plasma; however, tissue exposure of the various darolutamide, S,S-darolutamide and S,R-darolutamide were much lower as compared to plasma.

Conclusion: In lieu of the human pharmacokinetic data, although the administration of diastereomeric darolutamide was justified, it is proposed to delineate the clinical pharmacokinetics of S,R-darolutamide and S,S-darolutamide relative to darolutamide in future clinical pharmacology studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1872312814666200521091236DOI Listing
May 2020

Enantioselective LC-ESI-MS/MS method for quantitation of (-)-lumefantrine and (+)-lumefantrine in mice plasma and application to a pharmacokinetic study.

Biomed Chromatogr 2020 Sep 8;34(9):e4879. Epub 2020 Jun 8.

Drug Metabolism and Pharmacokinetics, Department of Analytical Chemistry, Jubilant Biosys Ltd, Bangalore, India.

We developed and validated a simple, sensitive, selective, and reliable LC-MS/MS-ESI method for the direct quantitation of lumefantrine (LFN) enantiomers [(-)-LFN and (+)-LFN] in mice plasma as per regulatory guideline. LFN enantiomers and carbamazepine (internal standard) were extracted from mice plasma using Strata X SPE (solid-phase extraction) cartridges. Good resolution between enantiomers was achieved on a Chiralpak IA-3 column using an isocratic mobile phase (0.1% of diethyl amine in methanol), which was delivered at a flow rate of 0.8 mL/min. Detection and quantitation were performed using multiple reaction monitoring mode following the transitions m/z 530.27 → 512.30 and 237.00 → 194.00 for LFN enantiomers and the internal standard, respectively, in the positive-ionization mode. The proposed method provided accurate and reproducible results over the linearity range of 2.39-895 ng/mL for each enantiomer. The intra- and inter-day precisions were in the range of 1.03-6.14 and 6.36-8.70 and 2.03-4.88 and 5.82-11.5 for (-)-LFN and (+)-LFN, respectively. Both (-)-LFN and (+)-LFN were found to be stable under different stability conditions. The method was successfully used to delineate stereoselective pharmacokinetics of LFN enantiomers in mice after an oral administration of rac-LFN (20 mg/kg). The pharmacokinetic results indicated that the disposition of LFN enantiomers was stereoselective in mice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/bmc.4879DOI Listing
September 2020

Critical Assessment of Pharmacokinetic Drug-Drug Interaction Potential of Tofacitinib, Baricitinib and Upadacitinib, the Three Approved Janus Kinase Inhibitors for Rheumatoid Arthritis Treatment.

Drug Saf 2020 08;43(8):711-725

Kenox Pharmaceuticals Inc., Jersey City, NJ, USA.

The introduction of novel, small-molecule Janus kinase inhibitors namely tofacitinib, baricitinib and upadacitinib has provided an alternative treatment option for patients with rheumatoid arthritis outside of traditional drugs and expensive biologics. This review aimed to critically assess the drug-drug interaction potential of tofacitinib, baricitinib and upadacitinib and provide a balanced perspective for choosing the most appropriate Janus kinase inhibitor based on the needs of patients with rheumatoid arthritis including co-medications and renal/hepatic impairment status. Based on the critical assessment, all three approved Janus kinase inhibitors generally provide a favourable opportunity for co-prescription with a plethora of drugs. While cytochrome P450 3A4-related inhibition or induction altered the exposures (area under the curve) of tofacitinib and upadacitinib, it did not impact the exposure of baricitinib. Transporter drug-drug interaction studies revealed that the disposition of baricitinib was altered with certain transporter inhibitors as compared with either tofacitinib or upadacitinib. Adjustment of tofacitinib or baricitinib dosages but not that of upadacitinib is required with the progression of renal impairment from a mild to a severe condition. While the dosage of tofacitinib needs to be adjusted for patients with moderate hepatic impairment status, it is not the case for either baricitinib or upadacitinib. Assessment of the drug-drug interaction potential suggests that tofacitinib, baricitinib and upadacitinib generally show a favourable disposition with no perpetrator activity; however, as victim drugs, they show subtle pharmacokinetic differences that may be considered during polypharmacy. Moreover, careful choice of the three drugs could be made in patients with rheumatoid arthritis with varying degrees of renal/hepatic impairments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s40264-020-00938-zDOI Listing
August 2020

Protein Binding and Stability of Drug Candidates: The Achilles' Heel in In Vitro Potency Assays.

Eur J Drug Metab Pharmacokinet 2020 Aug;45(4):427-432

Department of Innovation and Technology, Jubilant Life Sciences, D-12 Sector 59a, Noida, Uttar Pradesh, 201301, India.

In the present scenario of drug discovery, several screening filters ensure a rigorous nomination of clinical candidates. One of these screens is the determination of IC, the concentration of drug at half-maximal inhibitory concentration, also known as a potency assay. However, various nuances pertaining to the design, execution, and interpretation of in vitro potency results suggest a sizeable opportunity for the generation of erroneous data. The focus areas of this article include: (1) examining the requirement for the addition of serum albumin in in vitro potency assays, (2) problems encountered with cell lysates, and (3) drug candidate stability concerns during in vitro potency assays/high-throughput screening. Based on this assessment, the interpretation of the data generated using cell-based systems (i.e., lysates with or without the addition of fetal bovine serum) should be carried out with caution for in vitro potency testing, and the inclusion of a correction factor for non-specific protein binding should be considered. The addition of serum albumin to a cell-free system should be restricted to drugs having high protein binding (≥ 90%). Additionally, stability assessment of analytes should be considered to avoid dubious in vitro potency outcomes due to degraded material or active metabolite(s).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13318-020-00619-3DOI Listing
August 2020

International Normalized Ratio-Dependent Clearance of Dexmedetomidine: Possible Clinical Implications.

Anesth Analg 2020 05;130(5):e153

Drug Development, Kenox Pharmaceuticals, Inc, Monmouth Junction, New Jersey,

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1213/ANE.0000000000004694DOI Listing
May 2020

Incurred sample reanalysis of cefuroxime in rabbit ocular tissues-A case study.

Biomed Chromatogr 2020 Feb 17;34(2):e4737. Epub 2020 Jan 17.

Drug Metabolism and Pharmacokinetics, Yeshwanthpur, Bangalore, India.

In this paper, we present the incurred sample reanalysis (ISR) data for cefuroxime in various ocular tissues of rabbits. Based on the cefuroxime concentration vs. time profile in various ocular tissues, three chosen time points enabled ISR assessment. Cefuroxime was quantitated in the ocular tissues using a published liquid chromatography-electrospray ionization/tandem mass spectrometry method operated under the multiple reaction-monitoring mode in positive ion mode. Regardless of the ocular tissue, the linearity range was 12.7-2760 ng/ml with a correlation coefficient (r ) of ≥0.996. All of the ISR samples representing various ocular tissues met the acceptance criteria. To the best of our knowledge, this is the first report showing the ISR of ocular tissues in any species.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/bmc.4737DOI Listing
February 2020

Pronounced influence of presystemic metabolism on the metabolic disposition of imrecoxib in renally impaired patients.

Eur J Clin Pharmacol 2020 03 3;76(3):469-471. Epub 2020 Jan 3.

Department of Innovation and Technology, Jubilant Life Sciences, Sector 59 (D-10), Noida, Uttar Pradesh, India.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00228-019-02824-9DOI Listing
March 2020

Stability-indicating HPLC method for acyclovir and lidocaine in topical formulations.

Biomed Chromatogr 2020 Mar 12;34(3):e4751. Epub 2020 Jan 12.

Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, USA.

A simple, rapid and accurate stability-indicating HPLC assay was developed for the determination of acyclovir and lidocaine in topical formulations. Chromatographic separation of acyclovir and lidocaine was achieved using a reversed-phase C column and a gradient mobile phase (20 mm ammonium acetate pH 3.5 in water and acetonitrile). The degradation products of acyclovir and lidocaine in the samples were analyzed by ultra performance liquid chromatography-time of flight mass spectrometry. The HPLC method successfully resolved the analytes from the impurities and degradation products in the topical formulation. Furthermore, the method detected the analytes from the human skin leachables following the extraction of the analytes in the skin homogenate samples. The method showed linearity over wide ranges of 5-500 and 10-200 μg/ml for acyclovir and lidocaine in the topical product, respectively, with a correlation coefficient (r ) >0.9995. The relative standard deviations for precision, repeatability, and robustness of the method validation assays were <2%. The skin extraction efficiency for acyclovir and lidocaine was 92.8 ± 0.7% and 91.3 ± 3.2%, respectively, with no interference from the skin leachables. Thus, simultaneous quantification of acyclovir and lidocaine in the topical formulations was achieved.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/bmc.4751DOI Listing
March 2020

Relevance of preclinical rodent pharmacokinetics in the selection of a companion antibiotic for combining with beta-lactamase inhibitor.

Xenobiotica 2020 Jul 2;50(7):815-821. Epub 2019 Dec 2.

Department of Drug Metabolism and Pharmacokinetics, Zydus Research Centre, Ahmadabad, India.

Recent approvals of beta-lactamase inhibitor (BLI) drug in combination with cephalosporins/penems have provided the right impetus for novel BLIs. One important research question, hitherto not addressed, is pertaining to the relevance of preclinical pharmacokinetics for pairing the antibiotic with existing/novel BLI.Two BLI combination drugs: (a) approved (i.e. ceftazidime/avibactam); (b) clinical development (i.e. cefepime/zidebactam) were explored to provide insights to address the research question.Individual intravenous dosing of ceftazidime, avibactam, cefepime and zidebactam was done at 1 mg/kg by intravenous route in Balb/c mice and Wistar rats. Serial blood samples were collected and analysed by LC-MS/MS method.Examination of the ratios of pharmacokinetic parameters (CL, and ) for individual drugs in combinations (for instance, CL (ceftazidime)/CL (avibactam); CL (cefepime)/CL (zidebactam)) suggested that the pharmacokinetic data gathered in rats were generally within 0.5- to 2-fold; but mouse data revealed larger disparity for (0.11- to 8.25-fold) or CL (0.49- to 4.03-fold).The observed ratio for CL/ observed in rats agreed with corresponding human ratios for the pairwise comparison of the individual drugs in the combinations.Retrospectively, current pharmacokinetic findings suggest rat pharmacokinetic data may aid the combination of BLI with an appropriate antibiotic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/00498254.2019.1696494DOI Listing
July 2020

A review of bioanalytical methods for chronic lymphocytic leukemia drugs and metabolites in biological matrices.

Biomed Chromatogr 2020 Jan 26;34(1):e4742. Epub 2019 Dec 26.

Jubilant Biosys, 2nd Stage, Bangalore, India.

Quantitation of drugs used for the treatment of chronic lymphocytic leukemia in various biological matrices during both pre-clinical and clinical developments is very important, often in routine therapeutic drug monitoring. The first developed methods for quantitation were traditionally done on LC in combination with either UV or fluorescence detection. However, the emergence of LC with mass spectrometry in tandem in early 1990s has revolutionized the quantitation as it has provided better sensitivity and selectivity within a shorter run time; therefore it has become the choice of method for the analysis of various drugs. In this article, an overview of various bioanalytical methods (HPLC or LC-MS/MS) for the quantification of drugs for the treatment of chronic lymphocytic leukemia, along with applicability of these methods, is given.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/bmc.4742DOI Listing
January 2020

Stereoselective Pharmacokinetic Disposition of Ketorolac Following Drug Administration to Periarticular Tissues in Patients.

Anesth Analg 2020 01;130(1):e33-e34

Department of Innovation & Technology, Jubilant Life Sciences, Noida, Uttar Pradesh, India,

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1213/ANE.0000000000004506DOI Listing
January 2020

Role of Ceramides in Drug Delivery.

AAPS PharmSciTech 2019 Aug 13;20(7):287. Epub 2019 Aug 13.

Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, Alabama, 36849, USA.

Ceramides belong to the sphingolipid group of lipids, which serve as both intracellular and intercellular messengers and as regulatory molecules that play essential roles in signal transduction, inflammation, angiogenesis, and metabolic disorders such as diabetes, neurodegenerative diseases, and cancer cell degeneration. Ceramides also play an important structural role in cell membranes by increasing their rigidity, creating micro-domains (rafts and caveolae), and altering membrane permeability; all these events are involved in the cell signaling. Ceramides constitute approximately half of the lipid composition in the human skin contributing to barrier function as well as epidermal signaling as they affect both proliferation and apoptosis of keratinocytes. Incorporation of ceramides in topical preparations as functional lipids appears to alter skin barrier functions. Ceramides also appear to enhance the bioavailability of drugs by acting as lipid delivery systems. They appear to regulate the ocular inflammation signaling, and external ceramides have shown relief in the anterior and posterior eye disorders. Ceramides play a structural role in liposome formulations and enhance the cellular uptake of amphiphilic drugs, such as chemotherapies. This review presents an overview of the various biological functions of ceramides, and their utility in topical, oral, ocular, and chemotherapeutic drug delivery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1208/s12249-019-1497-6DOI Listing
August 2019

Use of sorbitol as pharmaceutical excipient in the present day formulations - issues and challenges for drug absorption and bioavailability.

Drug Dev Ind Pharm 2019 Sep;45(9):1421-1429

a Department of Drug Discovery and Development , Harrison School of Pharmacy, Auburn University , AL , USA.

Sorbitol is a popular sugar alcohol which has been used as an excipient in formulations of various drugs. Although from a safety perspective the presence of sorbitol in drug formulations does not raise a concern, reports have emerged and these suggest that sorbitol in drug formulations may alter oral absorption and bioavailability of certain drugs. The focus of this article was to review the published literature of various drugs where pharmacokinetic data has been reported for the drug alone drug administered with sorbitol and provide perspectives on the pharmacokinetic findings. Interestingly, for BCS class I drugs such as theophylline, metoprolol, the oral absorption, and bioavailability were generally not affected by sorbitol. However, theophylline oral absorption and bioavailability were decreased when sustained release formulation was used in place of immediate release formulation. For drugs such as risperidone (BCS class II) and lamivudine and ranitidine (BCS class III), the solution formulations showed diminished oral bioavailability in presence of sorbitol, whereas cimetidine and acyclovir (BCS class III), did not show any changes in pharmacokinetic profiles due to sorbitol. Finally, the presence of activated charcoal with sorbitol showed different pharmacokinetic outcome for BCS class I and II drugs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/03639045.2019.1640722DOI Listing
September 2019

Combination of flavonoids with azole drugs for fungal infections: key pharmacokinetic challenges.

Future Microbiol 2019 06 4;14:733-738. Epub 2019 Jul 4.

Department of Innovation & Technology, Jubilant Life Sciences, D-12, Sector 59, Noida, 201301, Uttar Pradesh, India.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/fmb-2019-0109DOI Listing
June 2019

Comment on: Pharmacokinetics and Safety of Recombinant Human Interleukin-1 Receptor Antagonist GR007 in Healthy Chinese Subjects.

Eur J Drug Metab Pharmacokinet 2019 10;44(5):719-721

Innovation and Technology, Jubilant Life Sciences, D-12, Sector 59, Noida, Uttar Pradesh, India.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13318-019-00566-8DOI Listing
October 2019

Pharmacokinetic evaluation of differential drug release formulations of rabeprazole in dogs.

Drug Dev Ind Pharm 2019 Sep 20;45(9):1459-1467. Epub 2019 Jun 20.

a Bioanalytical/Drug Metabolism and Pharmacokinetics Laboratory , Zydus Research Centre , Ahmedabad , India.

To develop novel dual release prototype capsule formulations of rabeprazole and evaluation of pharmacokinetic properties relative to the reference product (Aciphex) in Beagle dogs. The dual release prototype formulations of rabeprazole were developed by preparing optimized mini-tablets core which was subsequently coated with barrier/enteric coating using standard excipients. Both novel prototype formulations were subjected for release and assay by HPLC-UV to assess long term stability. Single dose pharmacokinetic study used a single sequence three treatments crossover design. In Periods 1 and 2, four dogs received oral 20 mg dose of two prototype formulations. In Period 3, all dogs received a 20 mg oral dose of Aciphex reference product. There was a 1-week washout time between two successive periods. A quantitative analysis of rabeprazole/sulfide metabolite in plasma samples was performed using a validated LC-MS/MS assay and PK parameters were estimated by non-compartmental analysis. The stability of the prototype formulations was confirmed over a period of 24 months with an acceptable assay and dissolution data. One of the novel prototype formulations showed 70% oral bioavailability relative to the reference product. Despite a 30% reduced bioavailability, this showed 1 h delay in peak concentration, longer plasma residence time of rabeprazole (up to 12 h) and longer apparent elimination half-life. The use of a canine model has enabled the selection of a novel dual-release prototype formulation of rabeprazole for further clinical development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/03639045.2019.1628249DOI Listing
September 2019

Prediction of Human Pharmacokinetics of Fomepizole from Preclinical Species Pharmacokinetics Based on Normalizing Time Course Profiles.

AAPS PharmSciTech 2019 Jun 18;20(6):221. Epub 2019 Jun 18.

Drug Metabolism and Pharmacokinetics, Jubilant Biosys, Industrial Suburb, Yeshwanthpur, Bangalore, 560 022, India.

Fomepizole is used as an antidote to treat methanol poisoning due to its selectivity towards alcohol dehydrogenase. In the present study, the goal is to develop a method to predict the fomepizole human plasma concentration versus time profile based on the preclinical pharmacokinetics using the assumption of superimposability on simulated time course profiles of animals and humans. Standard allometric equations with/without correction factors were also assimilated in the prediction. The volume of distribution at steady state (Vss) predicted by simple allometry (57.55 L) was very close to the reported value (42.17 L). However, clearance (CL) prediction by simple allometry was at least 3-fold higher to the reported value (33.86 mL/min); hence, multiple correction factors were used to predict the clearance. Both brain weight and maximum life span potential could predict the CL with 1.22- and 1.01-fold difference. Specifically, the predicted Vss and CL values via interspecies scaling were used in the prediction of series of human intravenous pharmacokinetic parameters, while the simulation of human oral profile was done by the use of absorption rate constant (Ka) from dog following the applicability of human bioavailability value scaled from dog data. In summary, the findings indicate that the utility of diverse allometry approaches to derive the human pharmacokinetics of fomepizole after intravenous/oral dosing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1208/s12249-019-1434-8DOI Listing
June 2019

Simultaneous determination of bendamustine and γ-hydroxybendamustine in mice dried blood spots and its application in a mice pharmacokinetic study.

J Pharm Biomed Anal 2019 Sep 28;174:168-174. Epub 2019 May 28.

Drug Metabolism and Pharmacokinetics, Jubilant Biosys Ltd., Industrial Suburb, Yeshwanthpur, Bangalore, 560 022, India. Electronic address:

A selective, sensitive and rapid mice dried blood spot (DBS) method has been developed and validated for the simultaneous quantification of bendamustine (BM) and γ-hydroxy-bendamustine (HBM) as per regulatory guidelines using an LC-MS/MS. Quality control, calibration curve and study sample DBS cards were sonicated with 5% formic acid in water before extraction with ethyl acetate enriched with internal standard (I.S.). The organic layer was evaporated and residue was reconstituted in 0.1% formic acid in acetonitrile for LC-MS/MS analysis. Chromatographic resolution of both analytes (BM and HBM) and the I.S. (loperamide) was achieved on an Atlantis dC column using 0.2% formic acid:acetonitrile (25:75, v/v) as an eluant delivered at a constant flow-rate of 0.5 mL/min. The total chromatographic run time was 3.2 min. The MS/MS ion transitions monitored were m/z 358.0 → 228.0, 374.0 → 338.0 and 477.0 → 210.0 for BM, HBM and the I.S, respectively. The assay was linear in the range of 5.65-2544 ng/mL for both BM and HBM. The within-run and between-run accuracy and within-run and between-run precision were in the range of 0.96-1.00 and 1.36-9.94%, respectively for BM; 0.88-1.03 and 4.57-11.7%, respectively for HBM on mice DBS cards. Stability studies showed that both analytes were stable at room temperature for 7 days and at -80 °C for 55 days on DBS cards. The validated DBS method has been applied to a pharmacokinetic study in mice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jpba.2019.05.052DOI Listing
September 2019

Uptake and pharmacokinetics of cefuroxime in rabbits after intravitreal, intracameral, and topical dosing: relevance to human ocular injection of cefuroxime.

Xenobiotica 2020 Mar 19;50(3):339-345. Epub 2019 Jun 19.

Drug Metabolism and Pharmacokinetics, Industrial Suburb, Yeshwanthpur, Bangalore, India.

Cefuroxime is one of the widely used antibiotics. The objective of this study was to determine pharmacokinetics and disposition in various ocular tissues following topical (TOP), intracameral (IC) and intravitreal (IVT) administration of cefuroxime to rabbits.Following TOP, IC and IVT dosing plasma and various ocular tissues (aqueous humor (AH), vitreous humor (VH), conjunctiva, trabecular mesh (TM), lens and retina-choroid (RC)) were collected and analyzed to understand the disposition of cefuroxime. Postintravenous administration plasma samples were collected to determine the systemic pharmacokinetics.Post-TOP dosing cefuroxime concentrations were observed only in conjunctiva up to 48 h. IC administration showed cefuroxime concentrations in AH up to 8 h; in conjunctiva, TM and plasma, the concentration lasted up to 4 h and in RC and VH till 1 h. IVT administration of cefuroxime showed concentrations in all ocular tissues (up to 8 h) and lasted up to 48 h except in conjunctiva and RC.There was evidence that the mechanism(s) of cefuroxime entry into the eye by via IVT, IC and TOP routes is clearly different. The present ocular tissue data may aid clinicians for considering appropriate choice in the treatment of post-operative ocular complications due to bacterial infections including endophthalmitis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/00498254.2019.1624872DOI Listing
March 2020

Stereoselective pharmacokinetics and tissue distribution of levodropropizine after administration of pure levodropropizine and the -dropropizine to Sprague-Dawley rats.

Xenobiotica 2020 Feb 10;50(2):135-144. Epub 2019 May 10.

Drug Metabolism and Pharmacokinetics, Jubilant Biosys, Bangalore, India.

Levodropropizine (LDP) is a non-opioid anti-tussive. The stereoselective pharmacokinetics and tissue distribution (TD) of LDP vs. dextrodropropizine (DDP) have been characterized after oral and (IV) administration of LDP and -dropropozine in rats.Oral/IV doses of 50/5.0 mg/kg and 25/2.5 -dropropizine and LDP were employed. TD study focused on tissues such as liver, lung and kidney. Blood samples were collected for pharmacokinetic and TD evaluation. Validated methods were used to quantitate LDP, DDP and -dropropizine.No stereoselectivity in pharmacokinetics was observed between LDP vs. DDP following -dropropizine. However, LDP pharmacokinetics after LDP administration (oral/IV) appeared to be different compared to LDP derived from -dropropizine.TD data were similar between the two enantiomers regardless of oral/IV -dropropizine administration. When LDP alone was administered, levels were comparable to those derived for LDP from -dropropizine after oral/IV. However, in the lung and kidney tissues, the exposure after oral dosing was higher for LDP alone as compared to LDP from -dropropizine.In summary, complete characterization of stereoselective pharmacokinetics and TD of -dropropizine has been reported after oral/IV routes. It was evident that the presence of DDP, increased the plasma/tissue exposure of LDP which was evident after oral -dropropizine dosing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/00498254.2019.1599148DOI Listing
February 2020

Lack of inhibition of CYP2C8 by saroglitazar magnesium: In vivo assessment using montelukast, rosiglitazone, pioglitazone, repaglinide and paclitaxel as victim drugs in Wistar rats.

Eur J Pharm Sci 2019 Mar 8;130:107-113. Epub 2019 Jan 8.

Zydus Research Centre, Cadila Healthcare Ltd., Satellite cross road, Ahmadabad, Gujarat, India.

Saroglitazar, a PPAR αҮ agonist, is currently undergoing global development for the treatment of NASH and other indications. Saroglitazar showed CYP2C8 inhibition in human liver microsomes (IC: 2.9 μM). The aim was to carry out drug-drug interaction (DDI) studies in Wistar rats using saroglitazar (perpetrator drug) with five CYP2C8 substrates. Also, the in vitro CYP2C8 inhibitory potential of saroglitazar in rat liver microsomes (RLM) was evaluated to justify use of preclinical model. The oral pharmacokinetics of various CYP2C8 substrates; montelukast, rosiglitazone, pioglitazone, repaglinide and intravenous pharmacokinetics of paclitaxel was assessed in the presence/absence of oral saroglitazar (4 mg/kg) in Wistar rats. A separate study was performed to assess the oral pharmacokinetics of saroglitazar. Serial blood samples were collected from all studies and the harvested plasma were stored frozen until bioanalysis. LC-MS/MS was used for the analysis of various analytes; concentration data was subjected to noncompartmental pharmacokinetic analysis. Statistical tests (unpaired t-test) were employed to judge the level of DDI. Generally, the pharmacokinetics of CYP2C8 substrates was not affected by the concomitant intake of saroglitazar as judged by the overall exposure (AUC and AUC) and elimination half-life. The CYP2C8 IC of 4.5 μM in RLM for saroglitazar, supported the use of rats for this DDI study. In conclusion, pharmacokinetic data of diverse CYP2C8 substrates suggested that coadministration of saroglitazar did not cause clinically relevant DDI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejps.2019.01.005DOI Listing
March 2019

Comment on: Pharmacokinetics, Pharmacodynamics, and Safety of the Novel Calcimimetic Agent Evocalcet in Healthy Japanese Subjects: First-in-Human Phase I Study.

Clin Drug Investig 2019 01;39(1):105-107

Zydus Research Centre, a Division of Cadila Healthcare Ltd, Sarkhej-Bavla NH 8A, Moraiya, Ahmedabad, Gujarat, 382 210, India.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s40261-018-0738-xDOI Listing
January 2019

Differential pharmacokinetic drug-drug interaction potential of eletriptan between oral and subcutaneous routes.

Xenobiotica 2019 Oct 27;49(10):1202-1208. Epub 2018 Dec 27.

a Bioanalytical/Drug Metabolism and Pharmacokinetics Laboratory , Zydus Research Centre , Ahmedabad , India.

1. Pharmacokinetic drug-drug interaction (DDI) data is important from a label claim either in combination drug usage or in polypharmacy situation. 2. Eletriptan undergoes first pass related metabolism through CYP3A4 enzyme to form pharmacologically active N-desmethyl metabolite. 3. Differential DDI interaction of the concomitant oral dosing of ketoconazole (20.1 mg/kg), a CYP3A4 inhibitor, with oral (4.2 mg/kg) or subcutaneous dose (2.1 mg/kg) of eletriptan was evaluated in male Sprague Dawley rats. Serial pharmacokinetic samples were collected and simultaneously analysed for eletriptan/N-desmethyl eletriptan using validated assay. Non-compartmentally derived pharmacokinetic parameters for various treatments were analysed statistically. 4. After oral eletriptan in presence of ketoconazole, (40 vs. 32 ng/mL alone) and (81 vs. 24 ng.h/mL alone) of eletriptan increased; the formation of N-desmethyl eletriptan decreased (=1.1 ng/mL, 3.9%) with ketoconazole as compared to without treatment (=3.7 ng/mL, 11.2%). After subcutaneous eletriptan in presence of ketoconazole, there was no change in (153 vs.152 ng/mL) or (267 vs. 266 ng.h/mL) of eletriptan. Formation of N-desmethyl eletriptan after the subcutaneous dose was determined at few intermittent time points with/without ketoconazole. 5. Preclinical data support differential DDI of eletriptan when dosed oral vs. subcutaneous, which need to be evaluated in a clinical setting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/00498254.2018.1540805DOI Listing
October 2019