Journal of Pharmacokinetics & Experimental Therapeutics
Open Access

Aside from typical pharmacokinetic studies in healthy volunteers, patients, and special subgroups, well-designed controlled studies using a wide range of dosages are required to produce credible doseresponse curves for therapeutic and harmful effects. Lower doses often have a better risk/benefit ratio than those suggested. In high dose/ concentration scenarios, secondary pharmacology of the drug and its active metabolites must be characterised in order to determine safety (adverse reactions and pharmacokinetic and pharmacodynamic drugdrug interactions) [1].

The enzyme systems responsible for a drug's metabolism must be identified, and then rational research of drug-drug and drug-disease interactions must be conducted, both in terms of efficacy and safety. During all phases of the drug's clinical development, factors responsible for changes in the functional expression of this enzyme system must be identified, and the safety and efficacy implications of these findings at the interethnic, inter-, and intraindividual levels must be thoroughly investigated. As a result, patient subgroup-specific dose regimens should be carefully developed to maximise the risk/benefit ratio for all patients [2-4].

Review

Because drugs act in a chiral environment, their pharmacokinetics and pharmacodynamics differ dramatically between enantiomers. It's important to look into the possibilities of interactions between a drug's enantiomers as well as enantioselective interactions. These should be thoroughly explored, and the choice to market a racemic combination or one of its enantiomers must be supported by scientific evidence. Population pharmacokinetics analysis is a method for examining the roles of many parameters that are thought to be clinically important for medication safety and efficacy. This paper discusses the general regulatory requirements and future perspectives for clinical pharmacokinetic data, including the dose-response relationship, metabolite activity, chirality, pharmaco genetics, and the value of population-based approaches to identify subsets of patient populations of pharmacokinetic interest, with examples [5]. After obtaining written informed consents, clinical and laboratory investigations which included physical examination, electrocardiogram (ECG) monitoring, chest X-ray test, and laboratory investigations (urinalysis, haematology, and serum biochemistry, serology, and pregnancy status) were carried out to confirm the eligibility of study participants. Screening and recruitment of study participants continued until the required number was achieved. All the recruited subjects were admitted in the clinical pharmacology unit well before time to meet the 10 h fasting condition before dosing. Clinical safety was assessed from the screening period till the end of the study through clinical examination, vital signs assessment, oral/axillary body temperature, 12-lead electrocardiogram (ECG) recording, blood glucose level (mg/ dL) measurement, chest X-ray (posterior-anterior view) recording, orthostatic hypotension measurement, clinical laboratory parameters (e.g. biochemistry, haematology, immunology and urine analysis), subjective symptomatology and monitoring of adverse events [6-7].

Existing Requirements and Future Views

Conducting bioequivalence trials without exposing a large number of healthy volunteers to demonstrate two highly variable (percent coefficient of variability greater than 30) test/reference (branded) drug products in different formulations to meet the standard 90 percent confidence interval criteria of relevant pharmacokinetic metrics between 0.80 and 1.25 and to keep the consumer risk below 5% has been a challenge. Many highly variable generic medicines' absorption, distribution, metabolism, and elimination can be considerably influenced by genetic variants encoding essential drug-metabolizing enzymes after delivery. This article summarises recent case studies and examples of using pharmacokinetic screening approaches to reduce the financial and ethical burden of recruiting larger numbers of subjects in bioequivalence trials to perform pharmacokinetic studies for formulations of highly variable drug products without expanding bioequivalence acceptance limits [8].

Pharmacokinetic simulation was performed to predict the pharmacokinetic profile of Sinococuline on Days 03, 05, 08 and 09 at 200, 400, 600 and 800 mg TID doses of AQCH. Individual plasma concentration data of Sinococuline at 100 mg dose was used for model development of pharmacokinetic simulation. The simulation was done using Phoenix Modelling by Phoenix Win Nonlin Version 8.2 using compartmental modelling approach. A total of 1000 iterations were used during prediction of pharmacokinetic profile for different dose levels [9]. The list of adverse events following active treatment of AQCH tablets or placebo is listed in . AQCH tablets were well tolerated in all the 5 cohorts. There were no clinically significant findings in the vital signs assessment, 12-lead ECG recording or the laboratory tests in any of the subjects in the study. No subject had a maximum on-treatment QTcB interval >450 ms while receiving AQCH or Placebo. There were no significant changes in QTc intervals after the dosing. The analysis of adverse events was carried out treatment-wise. There were no deaths or serious adverse events during the conduct of the study [10].

Adverse events that were likely to be related to the test formulation were assessed using the Naranjo algorithm. Haematology, serum biochemistry, and urinalysis were monitored on Days 01 and 10 for all the groups. Any abnormal laboratory result was followed up with repeat checks until it returned to normal. Laboratory abnormalities (outside the normal ranges) that first occurred or increased in intensity during follow-up were evaluated. Total 57 out of 60 subjects completed the study while 3 subjects were withdrawn from study due to adverse events

P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are well-known for their roles in drug-drug interactions (DDIs), limiting drug absorption, and preventing medicines with particular physicochemical qualities from penetrating the brain. Inhibition of P-gp/BCRP by gut medications has been shown to increase systemic exposure to substrate medicines. The feasibility of inhibiting P-gp/ BCRP at the blood-brain barrier and its ramifications were reviewed in a previous International Transporter Consortium (ITC) perspective. This ITC perspective expands on and covers pharmacological inhibition of P-gp/BCRP (also known as systemic) in the hepatic and renal systems, as well as whether there are any implications for substrate drug disposal. With an emphasis on biliary and active renal excretion pathways, this perspective highlights the clinical evidencebased recommendations for systemic P-gp and BCRP inhibitors of medicines. Curation of DDIs involving intravenously administered substrates or inhibitors; (2) in vitro-to-in vivo extrapolation of P-gpmediated DDIs at the systemic level; and (3) curation of drugs with information about the contribution of biliary excretion and related DDIs were all used to assess the clinical relevance of systemic P-gp and BCRP inhibition in the liver and kidney. This viewpoint supports a limited clinical DDI risk following P-gp or BCRP inhibition in the liver or kidney, based on the totality of evidence presented thus far [11].

Pharmacokinetic analysis

The pharmacokinetic parameters of capecitabine and its metabolites (5′-5′-DFCR. 5′- DFUR, and 5-FU) were determined from the concentration–time data using non-compartmental model of PKanalix software. The following parameters were estimated. Maximum plasma concentrations (Cmax) and time of their occurrence (Tmax) were determined from the observed highest concentration and its occurrence, respectively. AUC0-t is the area under the curve from time 0 to the last sampling time (t last) at which the concentration could be measured (Clast). MRTlast: mean residence time is from 0 to tlast (h). Volume of distribution (Vdobs) and clearance (Clobs) were calculated for capecitabine but not for the other metabolites [12].

Conclusion

Over the past ten years, capecitabine has been studied as a treatment of colorectal carcinoma, and in general, is considered to have an advantage in terms of overall survival in patients with metastatic colorectal cancer. For the purposes of this investigation, the pharmacokinetic parameters of capecitabine and its metabolites in colorectal cancer patients were reported. Despite using lower doses, capecitabine and its metabolites parameters were found to be similar to other studies except for the longer half-life found in our patients. In addition, lower doses of capecitabine showed acceptable response rate which might indicate that higher doses are not always necessary to achieve desired therapeutic effect. However further researches are needed to conclude this theory.

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