Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ZY-IL1 in Three Patients with Cryopyrin-Associated Periodic Syndromes.

We present the first results of the proof-of-concept phase 2a study of oral NLRP3 inflammasome inhibitor in subjects with cryopyrin-associated periodic syndromes (CAPS). Three adult subjects with a confirmed diagnosis of CAPS were enrolled and administered 50 mg of ZYIL1 twice daily for 7 days. A total of 5 treatment-emergent adverse events (TEAEs) were reported in 2 subjects. All 5 TEAEs were mild in severity and considered unrelated to the study drug. At steady state, the average plasma concentration and trough concentration ranged from 2.5 to 4.2 and 1.4 to 2.5 µg/mL, respectively. Inflammatory markers and disease activity (physician and patient global assessment score) decreased notably 12 hours post-last dose.

Safety, tolerability, pharmacokinetics, and pharmacodynamics of a novel kappa opioid receptor agonist ZYKR1: a randomized double-blind placebo-control phase 1 study in healthy adult human participants.

To perform first-in-human single-dose escalation trial of ZYKR1, which is a potent, selective, and peripherally-restricted kappa opioid receptor agonist, is the purpose of this study. This randomized, double-blind, placebo-controlled single ascending dose study conducted at Zydus Research Centre, Ahmedabad, India included healthy male participants aged 18-55 years and weighing > 50 kg. The primary objective was to evaluate the safety and tolerability of ZYKR1. The secondary objective was to evaluate the pharmacokinetics and pharmacodynamics (PD) of ZYKR1. Participants received ZYKR1 (0.5 - 6 mcg/kg) or placebo infused intravenously in 15 ± 1 min. Of total five dose groups (0.5 - 6 mcg/kg), each group included eight participants with six and two randomized to ZYKR1 and placebo, respectively. Three participants experienced six treatment-emergent adverse events (TEAEs); two were gastrointestinal disorders (nausea and vomiting at 2 mcg/kg); and four were related to the nervous system (headache (at 2 mcg/kg) and facial tingling, facial numbness and paresthesia (at 6 mcg/kg)); all TEAEs were mild and resolved without sequelae. The Cmax of ZYKR1 was achieved after 15 - 20 min of start of infusion. The mean exposures (Cmax and AUC0 - t) increased in a dose-proportional manner. The mean t1/2 ranged from 2.20 to 2.98 h across the dose range. Increase in the mean prolactin level was significantly higher in treatment groups compared with that in the placebo group. Intravenous ZYKR1 at doses up to 6 mcg/kg showed acceptable safety and tolerability and demonstrated a short half-life with principal route of excretion as renal. ZYKR1 displayed a potent PD effect reflected by increased prolactin levels, supporting further study in patients. Trial registration Clinical Trial Registry of India: CTRI/2018/07/014927. Date of registration: 18/07/2018.

Pharmacokinetics and Safety Evaluation of Single-Dose Saroglitazar Magnesium in Subjects with Hepatic Impairment.

Saroglitazar magnesium, a dual peroxisome proliferator-activated receptor agonist, is under evaluation for treating various liver conditions. While the pharmacokinetics (PK) of saroglitazar have been extensively studied in diverse preclinical models and healthy subjects, a comprehensive assessment of its PK behavior under conditions of hepatic impairment is lacking. In this Phase 1, open-label, parallel-group study, the PK of a single dose of 4-mg saroglitazar magnesium was investigated in subjects having varying degrees of hepatic impairment with and without portal hypertension compared with appropriately matched individuals having normal hepatic function. Treatment-emergent adverse events for safety were also evaluated. Thirty-two subjects were enrolled in the hepatic-impaired groups and 23 subjects in the normal hepatic function group. Mild and moderate hepatic impairment did not significantly affect the PK of saroglitazar, compared with normal hepatic function. Although severe hepatic impairment did not alter maximum observed plasma concentration and half-life; saroglitazar exposure (area under the plasma concentration-time curve from time 0 to infinity) increased 3-fold, while the clearance was 61% lower compared to the subjects with normal hepatic function. This may require close monitoring or dose adjustments in individuals with severe hepatic impairment. A single oral dose of saroglitazar magnesium 4 mg was found to be safe and well tolerated in subjects with varying degrees of hepatic function.

A Food-Effect Study to Evaluate the Oral Bioavailability of Desidustat.

This randomized, single-treatment, 2-sequence study evaluated the food effect on oral bioavailability of desidustat. Healthy adult male and female subjects were enrolled and randomly assigned to receive desidustat 50 mg orally in a fasting state in one period and a fed state in the other period. A standardized high-fat, high-calorie breakfast was served to assess the food effect. The pharmacokinetic results showed that the time to maximum blood concentration of desidustat was delayed significantly (P < .0001) in the fed state compared to the fasting state. The ingestion of food decreased the maximum blood concentration (Cmax ) compared to the fasting state (mean Cmax , 3248 ng/mL in the fed state vs 5496 ng/mL in the fasting state). The geometric mean ratio of fed/fasting for log-normal (ln) Cmax was 57. The exposure decreased in the fed state compared to the fasting state (mean area under the concentration-time curve [AUC] over the dosing interval, 25 559 ng â€¢ h/mL in the fed state versus 33 705 ng â€¢ h/mL in the fasting state; mean AUC from time 0 to infinity [AUC0-∞ ], 25,910 ng â€¢ h/mL in the fed state vs 34 233 ng â€¢ h/mL in the fasting state). The geometric mean ratio of fed/fasting for lnAUC from time 0 to the last quantifiable concentration and ln AUC0- ∞  was 77 and 76, respectively. The 90%CI of fed/fasting ratio of the geometric mean of lnCmax , AUC over the dosing interval, and AUC0-∞ of desidustat 50 mg did not fall within 80%-125% margin. Therefore, the absence of food effect could not be established. It can be inferred that food has a significant effect on the oral absorption of desidustat. Therefore, food must not be consumed 1 hour before and 2 hours after the oral administration of desidustat.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Oral NLRP3 Inflammasome Inhibitor ZYIL1: First-in-Human Phase 1 Studies (Single Ascending Dose and Multiple Ascending Dose).

ZYIL1 is a nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain-containing 3 (NLRP3) inflammasome inhibitor, which prevents NLRP3-induced apoptosis-associated speck-like protein containing a caspase activation and recruitment domain oligomerization, thus inhibiting NLRP3 inflammasome pathway. We investigated the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of ZYIL1 after single and multiple doses in healthy subjects. The subjects aged 18-55 years were enrolled in 2 different studies: single and multiple ascending dose. Blood/urine samples were collected at designated time points for pharmacokinetic and pharmacodynamic analysis. In the single-ascending-dose study, 30 subjects were enrolled (6 subjects each in 5 dose groups). One adverse event was reported during the study. ZYIL1 was well absorbed with median time to maximum plasma concentration at 1-1.5 hours. The exposures were dose proportional across the dose ranges. ZYIL1 is excreted as an unchanged form via the renal route. The mean elimination half-life was 6-7 hours. In the multiple-ascending-dose study, 18 subjects were enrolled (6 subjects each in 3 dose groups). Eleven adverse events were reported by 6 subjects during the study. The accumulation index at steady state for area under the plasma concentration-time curve indicated that ZYIL1 has a marginal accumulation upon repeated dosing. Dose-proportional exposure was observed across the dose ranges. All subjects showed >90% interleukin (IL)-1ß inhibition in all dose groups for both studies. Inhibition in IL-1ß and IL-18 was observed throughout the 14 days of treatment in the multiple-dose study. The safety profile, rapid absorption, marginal accumulation, and significant inhibition of IL-1ß and IL-18 level support its development for the management of inflammatory disorders.

Nonclinical Pharmacokinetic Evaluation of Desidustat: a Novel Prolyl Hydroxylase Inhibitor for the Treatment of Anemia.

BACKGROUND AND OBJECTIVES: Desidustat is a novel prolyl hydroxylase domain (PHD) inhibitor for the treatment of anemia. The objective of this study was to investigate the pharmacokinetics and drug-drug interaction properties of desidustat using in vitro and in vivo nonclinical models. METHODS: In vitro, Caco2 cell permeability, plasma protein binding, metabolism, cytochrome P450 (CYP) inhibition, and CYP induction were examined. In vivo, pharmacokinetic studies of oral bioavailability in mice, rats, dogs and monkeys, dose linearity, tissue distribution, and excretion in rats were conducted. RESULTS: In Caco-2 cells, the apparent permeability of desidustat was high at low pH and low at neutral pH. The oral bioavailability (%F) of desidustat was 43-100% with a median time to reach peak concentration (Tmax) of about 0.25-1.3 h across species. Desidustat displayed a low mean plasma clearance (CL) of 1.3-4.1 mL/min/kg (approximately 1.8-7.4% of hepatic blood flow), and the mean steady-state volume of distribution (Vss) was 0.2-0.4 L/kg (approximately 30-61% of the total body water). Desidustat showed a dose-dependent increase in exposures over the 15-100 mg/kg dose range. It was rapidly distributed in various tissues, with the highest tissue-to-blood ratio in the liver (1.8) and kidney (1.7). Desidustat showed high plasma protein binding and was metabolically stable in human liver microsomes, hepatocytes, and recombinant CYPs. It did not show significant inhibition of major drug-metabolizing CYP enzymes (IC50 > 300 µM) or the potential to induce CYP1A2 and CYP3A4/5 (up to 100 µM) in HepG2 cells. It may have minimal potential of clinical drug-drug interaction when used in combination with iron supplements or phosphate binders. Desidustat was primarily excreted unchanged in urine (25% of the oral dose) and bile (25% of the oral dose) in rats. The mean elimination half-life of desidustat ranged from 1.0 to 5.3 h and 1.3 to 5.7 h across species after intravenous and oral administration, respectively. CONCLUSION: Taken together, desidustat is well absorbed orally. It showed a dose-dependent increase in exposure, did not accumulate in tissue, and was eliminated via dual routes. It is metabolically stable, has minimal potential to cause clinical drug-drug interactions (DDIs), and demonstrates discriminable pharmacokinetic properties for the treatment of anemia.

Safety, pharmacokinetics, and antimalarial activity of the novel triaminopyrimidine ZY-19489: a first-in-human, randomised, placebo-controlled, double-blind, single ascending dose study, pilot food-effect study, and volunteer infection study.

BACKGROUND: New antimalarials with novel mechanisms of action are needed to combat the emergence of drug resistance. Triaminopyrimidines comprise a novel antimalarial class identified in a high-throughput screen against asexual blood-stage Plasmodium falciparum. This first-in-human study aimed to characterise the safety, pharmacokinetics, and antimalarial activity of the triaminopyrimidine ZY-19489 in healthy volunteers. METHODS: A three-part clinical trial was conducted in healthy adults (aged 18-55 years) in Brisbane, QLD, Australia. Part one was a double-blind, randomised, placebo-controlled, single ascending dose study in which participants enrolled into one of six dose groups (25, 75, 150, 450, 900, or 1500 mg) were randomly assigned (3:1) to ZY-19489 or placebo. Part two was an open-label, randomised, two-period cross-over, pilot food-effect study in which participants were randomly assigned (1:1) to a fasted-fed or a fed-fasted sequence. Part three was an open-label, randomised, volunteer infection study using the P falciparum induced blood-stage malaria model in which participants were enrolled into one of two cohorts, with participants in cohort one all receiving the same dose of ZY-19489 and participants in cohort two randomly assigned to receive one of two doses. The primary outcome for all three parts was the incidence, severity, and relationship to ZY-19489 of adverse events. Secondary outcomes were estimation of ZY-19489 pharmacokinetic parameters for all parts; how these parameters were affected by the fed state for part two only; and the parasite reduction ratio, parasite clearance half-life, recrudescent parasitaemia, and pharmacokinetic-pharmacodynamic modelling parameters for part three only. This trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12619000127101, ACTRN12619001466134, and ACTRN12619001215112). FINDINGS: 48 participants were enrolled in part one (eight per cohort for 25-1500 mg cohorts), eight in part two (four in each group, all dosed with 300 mg), and 15 in part three (five dosed with 200 mg, eight with 300 mg, and two with 900 mg). In part one, the incidence of drug-related adverse events was higher in the 1500 mg dose group (occurring in all six participants) than in lower-dose groups and the placebo group (occurring in one of six in the 25 mg group, two of six in the 75 mg group, three of six in the 150 mg group, two of six in the 450 mg group, four of six in the 900 mg group, and four of 12 in the placebo group), due to the occurrence of mild gastrointestinal symptoms. Maximum plasma concentrations occurred 5-9 h post-dosing, and the elimination half-life was 50-97 h across the dose range. In part two, three of seven participants had a treatment-related adverse event in the fed state and four of eight in the fasted state. Dosing in the fed state delayed absorption (maximum plasma concentration occurred a median of 12·0 h [range 7·5-16·0] after dosing in the fed state vs 6·0 h [4·5-9·1] in the fasted state) but had no effect on overall exposure (difference in area under the concentration-time curve from time 0 [dosing] extrapolated to infinity between fed and fasted states was -0·013 [90% CI -0·11 to 0·08]). In part three, drug-related adverse events occurred in four of five participants in the 200 mg group, seven of eight in the 300 mg group, and both participants in the 900 mg group. Rapid initial parasite clearance occurred in all participants following dosing (clearance half-life 6·6 h [95% CI 6·2-6·9] for 200 mg, 6·8 h [95% CI 6·5-7·1] for 300 mg, and 7·1 h [95% CI 6·6-7·6] for 900 mg). Recrudescence occurred in four of five participants in the 200 mg group, five of eight in the 300 mg group, and neither of the two participants in the 900 mg group. Simulations done using a pharmacokinetic-pharmacodynamic model predicted that a single dose of 1100 mg would clear baseline parasitaemia by a factor of 109. INTERPRETATION: The safety, pharmacokinetic profile, and antimalarial activity of ZY-19489 in humans support the further development of the compound as a novel antimalarial therapy. FUNDING: Cadila Healthcare and Medicines for Malaria Venture.

Simultaneous estimation of ZY-19489 and its active metabolite ZY-20486 in human plasma using LC-MS/MS, a novel antimalarial compound.

Aim: ZY-19489 is a new antimalarial drug candidate and selective LC-MS/MS method was established for estimation of ZY-19489 and its metabolite in human plasma. Materials & methods: LLE was employed for extraction, mass spectrometric quantification performed using positive ionization mode and DCP-IMP was used as an internal standard. The chromatographic separation was achieved using mobile phase 5 mM ammonium formate in water and 0.1% v/v ammonia solution in methanol:acetonitrile (90:10% v/v) and column Agilent Zorbex Extended C18, 3.5 µm, 100 × 4.6 mm with a 6-min run time. Results: The calibration curve of ZY-19489 was linear over range 1-500 ng/ml and 2-200 ng/ml for metabolite. Assay was reproducible, selective and devoid of matrix effect. Conclusion: The validated assay was implemented for clinical sample analysis derived from healthy human subjects and parasitemia-induced subjects.

Estimation of ZYKR1 in human urine and plasma utilizing LC-MS/MS positive electrospray ionization; a kappa opioid receptor (KOR) agonist.

ZYKR1, a short chain novel peptide with selective kappa opioid receptor agonist activity used as analgesics for the treatment of pain management. A sensitive and selective LC-MS/MS assay was developed and validated for estimation of ZYKR1 in human urine and plasma. ZY17258, an analogue compound was used as an internal standard. ZYKR1 was quantified using a selective reaction monitoring in electrospray ionization positive mode. The chromatographic separation was performed using mobile phase consisted of 0.05% v/v formic acid in water and methanol in gradient elution by analytical column Kinetex C8, 100 A°, 5 µm, 100 × 4.6 mm with 8.0 min analytical run time. Solid Phase extraction technique was used for purification of ZYKR1 and IS from human urine and plasma. The calibration curves were linear over range of 0.300 ng/mL to 300 ng/mL and 0.500 ng/mL to 500 ng/mL for human urine and plasma, respectively. No matrix effect and no significant carryover were observed. The extraction recovery was consistent and ranged from about 85% to 93% in human urine and in plasma respectively. Inter-day and intra-day accuracy (bias, %) and precision (CV, %) was -11.11 to 5.91 % and -2.25 to 6.65 % in human urine and -2.74 to 7.17 % and 2.24 to 15.18 % in plasma respectively were well within the acceptance criteria. Both the assays were devoid of endogenous matrix interference and commonly used concomitant drug interference. The validated assays were used for estimation of ZYKR1 from clinical pharmacokinetic study sample bioanalysis in healthy human subjects.

Discovery of a potent G-protein-coupled receptor 119 agonist for the treatment of type 2 diabetes.

The ever-growing prevalence of Type-2 diabetes in the world has an urgent need for multiple orally effective agents that can regulate glucose homeostasis. G-Protein coupled receptor 119 (GPR 119) agonists have demonstrated the glucose-dependent insulin secretion and showed beneficial effects on glycemic control in humans and/or relevant animal models. Herein, we describe our efforts towards identification of a potent and oral GPR 119 agonist 13c (ZY-G19), which showed in vitro potency in the cell-based assay and in vivo efficacy without exerting any significant signs of toxicity in relevant animal models.

A Phase 3, Randomized, Open-label, Noninferiority Trial Evaluating Anti-Rabies Monoclonal Antibody Cocktail (TwinrabTM) Against Human Rabies Immunoglobulin (HRIG).

BACKGROUND: Limited supply, cost and potential for severe adverse effects observed with the blood derived rabies immunoglobulin products has led to search for alternative therapies. This issue has been addressed by developing an anti-rabies monoclonal antibody cocktail. METHODS: This is a phase 3, randomized, open-label, noninferiority trial conducted in patients with World Health Organization (WHO) category III exposure with suspected rabid animal. Eligible patients were assigned to either the test arm, TwinrabTM (docaravimab and miromavimab) or the reference arm, human rabies immunoglobulin (HRIG; Imogam® Rabies-HT), in a ratio of 1:1. The primary endpoint was the comparison of responder rates between the 2 arms assessed as percentage of those with rabies virus neutralizing antibodies titers ≥0.5 IU/mL on day 14. RESULTS: A total of 308 patients were equally randomized into the 2 arms. In the per-protocol (PP) population, there were 90.21% responders in the TwinrabTM arm and 94.37% in the HRIG arm. The geometric mean of rapid fluorescent foci inhibition test titers in the PP on day 14 were 4.38 and 4.85 IU/mL, for the TwinrabTM and HRIG arms, respectively. There were no deaths or serious adverse events reported. CONCLUSIONS: This study confirmed that TwinrabTM is noninferior to HRIG in terms of providing an unbroken window of protection up to day 84. This trial in healthy adults with WHO category III exposure from suspected rabid animal also establishes the safety of TwinrabTM in patients with 1 WHO approved vaccine regimen (Essen). CLINICAL TRIALS REGISTRATION: CTRI/2017/07/009038.

Discovery of diaminopyrimidine-carboxamide derivatives as JAK3 inhibitors.

Selective inhibition of janus kinase (JAK) has been identified as an important strategy for the treatment of autoimmune disorders. Optimization at the C2 and C4-positions of pyrimidine ring of Cerdulatinib led to the discovery of a potent and orally bioavailable 2,4-diaminopyrimidine-5-carboxamide based JAK3 selective inhibitor (11i). A cellular selectivity study further confirmed that 11i preferentially inhibits JAK3 over JAK1, in JAK/STAT signaling pathway. Compound 11i showed good anti-arthritic activity, which could be correlated with its improved oral bioavailability. In the repeat dose acute toxicity study, 11i showed no adverse changes related to gross pathology and clinical signs, indicating that the new class JAK3 selective inhibitor could be viable therapeutic option for the treatment of rheumatoid arthritis.

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

Objectives: To develop novel dual release prototype capsule formulations of rabeprazole and evaluation of pharmacokinetic properties relative to the reference product (Aciphex®) in Beagle dogs. Methods: 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 in vitro 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. Results: 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. Conclusions: The use of a canine model has enabled the selection of a novel dual-release prototype formulation of rabeprazole for further clinical development.

Outcomes of Desidustat Treatment in People with Anemia and Chronic Kidney Disease: A Phase 2 Study.

BACKGROUND: Desidustat (ZYAN1) is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) that stimulates erythropoiesis. Stabilizing HIF via PHI is developing as a new therapeutic approach to treat anemia secondary to chronic kidney disease (CKD). This trial evaluated the safety, tolerability, and efficacy of Desidustat in adult CKD patients with anemia, who were not on dialysis. METHODS: This was a Phase 2, randomized, double-blind, 6-week, placebo-controlled, dose-ranging, safety and efficacy study. A total of 117 eligible patients were randomized to 4 arms: 100, 150, 200 mg, or placebo. The investigational product was administered every alternate day for 6 weeks in fasting conditions. The primary endpoint was change in hemoglobin (Hb) from baseline to week 6. RESULTS: Baseline demographics were well balanced among all the treatment arms. In the modified intent-to-treat (mITT) population, a mean Hb increase of 1.57, 2.22, and 2.92 g/dL in Desidustat 100, 150, and 200 mg arms, respectively, was observed post 6 weeks treatment. The responder rate (≥1 g/dL increase) was 66% in 100 mg, 75% in 150 mg, and 83% in 200 mg treatment arms, in the mITT population. Eighteen patients had at least one treatment emergent adverse event (TEAE), and 5 patients reported at least one drug-related mild TEAE. No death or serious adverse event was reported during the trial. CONCLUSION: There was dose-related increase in Hb across all doses compared to placebo in mITT and per-protocol populations. Desidustat also increased pharmacokinetic parameters Cmax and AUC in dose-related manner. There was no significant change in vital signs, electrocardiographic parameters, or safety laboratory values. Clinical Trial Registration Number CTRI/2017/05/008534 (registered on May 11, 2017).

Rats and rabbits as pharmacokinetic screening tools for long acting intramuscular depots: case study with paliperidone palmitate suspension.

Development of prodrug of 9-hydroxyrisperidone (paliperidone) long-acting intramuscular injection has enabled delivery over four-week time period with improved compliance. The key aim of this work was to establish a reliable preclinical model which may potentially serve as a screening tool for judging the pharmacokinetics of paliperidone formulation(s) prior to human clinical work. Sparse sampling composite study was used in rats, (Wistar/Sprague-Dawley (SD; n = 10)) and a serial blood sampling study design was used in rabbits (n = 4). Animals received intramuscular injection of paliperidone palmitate in the thigh muscle at dose of 16 (rats) and 4.5 mg/kg (rabbits). Samples were drawn in rats (retro-orbital sinus) and rabbits (central ear artery) and were analysed for paliperidone using liquid chromatography-mass spectrometry/ mass spectrometry (LC-MS/MS) assay. The plasma data was subjected to pharmacokinetic analysis. Following intramuscular injection of depot formulation in Wistar/SD rats and rabbits, absorption of paliperidone was slow and gradual with median value of time to reach maximum concentration (Tmax) occurring on day 7. The exposures (i.e. area under the curve (AUC; 0-28) days) were 18,597, 21,865 and 18,120 ng.h/mL, in Wistar, SD and rabbits, respectively. The clearance was slow and supported long half-life (8-10 days). Either one of the two models can serve as a research tool for establishing pharmacokinetics of paliperidone formulation(s).

Use of Cocktail Probe Drugs for Indexing Cytochrome P450 Enzymes in Clinical Pharmacology Studies - Review of Case Studies.

BACKGROUND: The cocktail approach of probing drug metabolizing enzymes, in particular cytochrome P450 (CYP) enzymes, is a cornerstone in clinical pharmacology studies. The first report of the famous "Pittsburg cocktail" has led the way for the availability of numerous cocktail substrate mixtures that provide options for indexing of CYP enzymes and/or evaluating the perpetrator capacity of the drug. OBJECTIVE: The key objectives were: 1) To collate, tabulate, and discuss the various cocktail substrates to determine specific CYP enzyme activity in clinical pharmacology studies with specific case studies; 2) To introspect on how the cocktail approach has withstood the test of time and evolved for enabling key decision(s); 3) To provide some futuristic views on the use of cocktail in drug discovery and development. METHOD: The review was compiled after consultation with databases such as PubMed (NCBI database) and Google scholar to source various published literature on cocktail approaches in drug development. RESULTS: In the reviewed case studies, CYP indexing was achieved using a single time point (differing for specific CYP enzyme) plasma determination of the metabolite to parent ratio for all CYP enzymes with the exception of CYP3A4/5, where multiple time points were required for exposure measurement of midazolam and its metabolite. Likewise, a single void of urine, for a specific time duration, has been utilized for the recovery measurements of parent and metabolite for CYP indexing purposes. CONCLUSION: The review provides a comprehensive list of various types of cocktail approaches and discusses some key considerations including the evolution of the cocktail approaches over time, perspectives and futuristic views for the use of probe drugs to aid the execution of clinical pharmacology studies and data interpretation.

Review of Clinical Pharmacokinetics of Avibactam, A Newly Approved non-ß lactam ß-lactamase Inhibitor Drug, In Combination Use With Ceftazidime.

Avibactam, a potent non-ß lactam ß-lactamase inhibitor, was recently approved in the USA for combination use with ceftazidime, a cephalosporin antibiotic drug. The addition of avibactam potentiates the antimicrobial drug ceftazidime, which otherwise would have been susceptible to ß-lactamases produced by variety of Gram negative pathogens. The focus of this review was to provide clinical pharmacokinetic data of avibactam to cover absorption, distribution, metabolism, and excretion aspects including any potential for avibactam to show drug-drug interactions in the clinic. Based on the review of the data, the pharmacokinetics of avibactam was generally stationary in the studied dosing regimen. The elimination half-life (approximately 1.4- 3.2 h) and volume of distribution at steady state (15.4-26.3 L) were found similar across the studies and therefore, provided the complementary pharmacokinetic attributes for combination use with ceftazidime. Renal excretion was the major pathway for the clearance of avibactam. In summary, any degree of renal dysfunction is expected to alter the pharmacokinetics of avibactam - this consideration should be factored in dosage adjustments while dosing in patients with renal impairment. Concomitant drugs that may influence renal mechanism of elimination of avibactam should be avoided and/or monitored for any impact on the pharmacokinetics of avibactam.