The use of pharmacokinetic and pharmacodynamic data in the assessment of drug safety in early drug development

The pharmaceutical industry continues to look for ways to reduce drug candidate attrition throughout the drug discovery and development process. A significant cause of attrition is due to safety issues arising either as a result of animal toxicity testing or in the clinical programme itself. A factor in the assessment of safety during early drug development is the pharmacokinetic profile of the compound. This allows safety data to be considered in the light of systemic drug exposure and therefore permits a quantitative assessment. This is particularly applicable when assessing the risk of a new chemical entity (NCE) in relation to safety parameters such as QT interval prolongation, where free plasma concentrations have been shown to be predictive of this property in relation to potency in preclinical testing. Prior to actual human exposure it is therefore important to be able to predict reliably the pharmacokinetic behaviour of an NCE in order to place such safety findings into a quantitative risk context. The emerging science of pharmacogenetics is likely to further our ability to assess the risk of NCEs to populations and individuals due to genetic variance. The drug metabolizing enzyme CYP2D6 has been recognized as providing the potential to result in widely differing systemic drug exposure in the patient population due to polymorphic expression. Further knowledge is likely to add to our understanding of population differences in exposure and response and aid in the identification of risk factors. One potential strategy for improving the effectiveness of the drug discovery process is to obtain clinical pharmacokinetic data more rapidly in order to assess more accurately the potential for both efficacy and safety of an NCE. Whilst procedures and technologies are available that allow this on the microdose scale, it is important that we recognize potential limitations of these approaches in order that they can be applied beneficially.     

A pharmacokinetic evaluation of five H1 antagonists after an oral and intravenous microdose to human subjects

AIMS

To evaluate the pharmacokinetics (PK) of five H₁ receptor antagonists in human volunteers after a single oral and intravenous (i.v.) microdose (0.1 mg).

METHODS

Five H₁ receptor antagonists, namely NBI-1, NBI-2, NBI-3, NBI-4 and diphenhydramine, were administered to human volunteers as a single 0.1-mg oral and i.v. dose. Blood samples were collected up to 48 h, and the parent compound in the plasma extract was quantified by high-performance liquid chromatography and accelerator mass spectroscopy.

RESULTS

The median clearance (CL), apparent volume of distribution (V_d) and apparent terminal elimination half-life (t_1/2) of diphenhydramine after an i.v. microdose were 24.7 l h⁻¹, 302 l and 9.3 h, and the oral C_max and AUC_0–∞ were 0.195 ng ml⁻¹ and 1.52 ng h ml⁻¹, respectively. These data were consistent with previously published diphenhydramine data at 500 times the microdose. The rank order of oral bioavailability of the five compounds was as follows: NBI-2 > NBI-1 > NBI-3 > diphenhydramine > NBI-4, whereas the rank order for CL was NBI-4 > diphenhydramine > NBI-1 > NBI-3 > NBI-2.

CONCLUSIONS

Human microdosing provided estimates of clinical PK of four structurally related compounds, which were deemed useful for compound selection.     

Accelerating drug development: methodology to support first‐in‐man pharmacokinetic studies by the use of drug candidate microdosing

Microdosing of experimental therapeutics in humans offers a number of benefits to the drug development process. Microdosing, conducted under an exploratory Investigational New Drug (IND) application, entails administration of a sub‐pharmacological dose of a new chemical entity (NCE) that allows for early evaluation of human pharmacokinetics. Such information can be pivotal for: (1) selecting a compound for full drug development from a small group of candidates; (2) defining the amount of material needed for early development; and (3) setting the initial Phase I dose regimen in humans. Appropriate safety studies must be conducted to support microdosing in humans, but the requirements are generally less extensive than those needed to support a traditional IND. To date, microdosing has not been broadly applied by the pharmaceutical industry due to concerns about analytical sensitivity and the possibility of non‐linear pharmacokinetics at extremely low doses. The primary method for detecting analytes following microdosing until now has been accelerator mass spectrometry, which is expensive, not generally available, and requires test agents to be radiolabeled. Presented in this report is an example of pharmacokinetics analysis using LC/MS/MS following microdosing of an experimental agent in cynomolgus monkeys. The results show good linearity in plasma pharmacokinetics for oral doses of 10 mg/kg (therapeutic dose) and 0.0005 mg/kg (microdose) of the test agent. The results also demonstrate the feasibility of applying standard laboratory analytics to support microdosing in humans and raise the possibility of establishing an animal model to screen for compounds having non‐linear pharmacokinetics at low dose levels. Drug Dev. Res. 68:14–22, 2007. © 2007 Wiley‐Liss, Inc.     

Comparison of the pharmacokinetic profile of metaclazepam in old and young volunteers

Summary A single-centre, open, Phase I-study comparison of the pharmacokinetics of a single dose of metaclazepam 10 mg, a new 1,4-benzodiazepine has been done in 10 older and 20 younger volunteers. No important age-related effect was found on the kinetics of metaclazepam or its N-desmethyl derivative, the principal metabolite in man.     

In vivo use of the CYP inhibitor 1‐aminobenzotriazole to increase long‐term exposure in mice

1‐Aminobenzotriazole (ABT) is a well‐known in vivo nonspecific inhibitor of cytochrome P450 (CYP) enzymes. An effective dosing regimen of ABT for a multiple‐administration study is needed to conduct pharmacological studies for proof‐of‐concept, although it has been established for single‐administration study, to characterize the pharmacokinetics of drug candidates. This study demonstrated a suitable dosing vehicle of ABT for continuous administration and increased exposure to antipyrine, which is a nonspecific probe of CYP, using ABT for a long period in mice. The dosing vehicle of ABT was 0.5% (w/v) hydroxypropyl methylcellulose and 0.5% (v/v) Tween 80 in N,N‐dimethylacetamide/20% hydroxypropyl‐β‐cyclodextrin aqueous solution (2:8, v/v) based on the duration of apparent solubility. After implantation of an ALZET osmotic pump with ABT, the plasma concentrations of ABT were maintained at more than 4.1 μg/ml over 336 h. Compared with the vehicle group, the CL_tot of antipyrine with ABT decreased to approximately one‐fourth, and the BA of antipyrine with ABT increased up to 3‐fold. In addition, the enhancement of exposure of antipyrine by ABT was maintained over the 336 h. The body weight, food consumption and hematological parameters of mice did not change with ABT administration for 16 days. These findings demonstrated that pretreatment of ABT can increase long‐term exposure using continuous administration with the ALZET osmotic pump in mice with no overt toxicity. It is concluded that the in vivo use of 1‐aminobenzotriazole can be applied to pharmacological studies for proof‐of‐concept, thus contributing to the selection of drug candidates at an early drug discovery stage. Copyright © 2016 John Wiley & Sons, Ltd.     

Improvement of cardiac efficacy and safety models in drug discovery by the use of stem cell-derived cardiomyocytes

Background: The pharmaceutical industry suffers from high attrition rates during late phases of drug development. Improved models for early evaluation of drug efficacy and safety are needed to address this problem. Recent developments have illustrated that human stem cell-derived cardiomyocytes are attractive for using as a model system for different cardiac diseases and as a model for screening, safety pharmacology and toxicology. Objective: In this review, we discuss contemporary drug discovery models and their characteristics for cardiac efficacy testing and safety assessment. Additionally, we evaluate various sources of stem cells and how these cells could potentially improve early screening and safety models. Conclusion: We conclude that human stem cells offer a source of physiologically relevant cells that show great potential as a future tool in cardiac drug discovery. However, some technical challenges related to cell differentiation and production and also to validation of improved platforms remain and must be overcome before successful application can become a reality.     

Pharmacokinetics of α-dihydroergocriptine in rats after single intravenous and single and repeated oral administrations

The pharmacokinetics of α-dihydroergocriptine methane sulphonate in rats were investigated using an HPLC method for the detection of unchanged α-dihydroergocriptine (DHEK) in plasma, organs (kidneys, heart, lungs, spleen, liver, and brain), and urine. The plasma profile of DHEK obtained after intravenous administration at a dose of 5 mg kg^?1 (as base) of DHEK methane sulphonate showed a three compartment pharmacokinetic model with an elimination half-life of 6.78 h. The kinetics of DHEK after a single oral administration at a dose of 20 mg kg^?1 (as base) showed two peaks: the second peak, at about 6 h, was probably due to an enterohepatic cycle. The disposition of DHEK consisted of an absorption half-life of 0.02 h, a distribution half-life of 2.15 h and an elimination half-life of 5.83 h. The pharmacokinetics of DHEK, after repeated oral administrations at the same dose, were similar to those after a single oral administration. The absolute bioavailability was 4.14% after a single oral administration and 3.95% after repeated oral administrations. The analysis of the organs showed that DHEK was rapidly absorbed and distributed in all tissues, mostly in lungs, kidneys, and liver, but it is interesting to observe that it also reached the brain. After repeated oral administrations plasma and tissue concentrations were similar to those obtained after a single administration; therefore it is possible to exclude the onset of autoinduction or accumulation phenomena of DHEK in rats' organs. Urinary excretion of the unchanged drug was low (0.38% of the administered dose in the intravenous route and 0.04% in the oral route), being in agreement with a low oral bioavailability and a rapid and extensive metabolism (first-pass effect).     

A framework to assess the translation of safety pharmacology data to humans

This article outlines a strategy for collecting accurate data for the determination of the sensitivity, specificity and predictive value of safety pharmacology models. This entails performing a retrospective analysis on commonly used safety pharmacology endpoints and an objective assessment of new non-clinical models. Such assessments require a systematic quantitative analysis of safety pharmacology parameters as well as clinical Phase I adverse events. Once the sensitivity, specificity and predictive capacity of models have been determined, they can be aligned within specific phases of the drug discovery and development pipeline for maximal impact, or removed from the screening cascade altogether. Furthermore, data will contribute to evidence-based decision-making based on the knowledge of the model sensitivity and specificity. This strategy should therefore contribute to the reduction of candidate drug attrition and a more appropriate use of animals. More data are needed to increase the power of analysis and enable more accurate comparisons of models e.g. pharmacokinetic/phamacodynamic (PK/PD) relationships as well as non-clinical and clinical outcomes for determining concordance. This task requires the collaboration and agreement of pharmaceutical companies to share data anonymously on proprietary and candidate drugs.     

Population pharmacokinetics of the 11β‐hydroxysteroid dehydrogenase type 1 inhibitor ABT‐384 in healthy volunteers following single and multiple dose regimens

ABT‐384 is a potent and selective inhibitor of 11β‐hydroxysteroid dehydrogenase type 1 (HSD‐1). The pharmacokinetics of ABT‐384 was evaluated in healthy volunteers in single‐dose (1, 8, 20, 50, 120 and 240 mg) and multiple‐dose studies (1, 2, 4, 8, 20, 30 and 100 mg once daily). Less than dose‐proportional pharmacokinetics of ABT‐384 was observed when ABT‐384 was administered at single doses lower than 8 mg. This nonlinear phenomenon disappeared after repeated doses. The dose‐normalized plasma concentration–time curves superposed across all dose groups on day 7, but not on day 1. This phenomenon cannot be explained by the half‐life of ABT‐384. Based on available data, the nonlinearity is likely due to binding of ABT‐384 to a high‐affinity‐low‐capacity site, such that this interaction was reflected in ABT‐384 pharmacokinetics. To characterize the pharmacokinetics of ABT‐384, a population pharmacokinetic model for ABT‐384 was constructed. The model provided reasonable fitting for both single‐ and multiple‐dose data. Further investigation is warranted to evaluate the disposition of ABT‐384 at low doses using a larger number of subjects. The constructed model would be useful in predicting ABT‐384 concentrations at different doses and guiding the selection of dosing regimens in further clinical trials. Copyright © 2014 John Wiley & Sons, Ltd.     

Structural insights into anticancer activity of D‐ring modified estrone derivatives using their lipophilicity in estimation of SAR and molecular docking studies

Many forms of breast carcinoma are hormone‐dependent and therefore development of novel aromatase inhibitors is of particular interest. Since brain metastases are frequent in patients with advanced breast carcinoma, one of the goals of modern drug development is the discovery of drugs with specific pharmacokinetic profile. High performance thin layer chromatography (HPTLC) is often used to determine lipophilicity of the molecules based on their retention constant. As a predictive analysis, multiple linear regression method was performed to connect pharmacokinetic‐dependent parameters with independent physicochemical properties such are: R_M⁰, TPSA and M_w of fourteen D‐ring modified oestrone derivatives. Additionally, docking studies were performed. Conducted correlation analysis indicates excellent dependence between experimental R _M parameter values and calculated values of pharmacokinetic parameters. Results show sufficient intestinal absorption of all the investigated molecules as well as moderate volumes of distribution and strong affinity for binding to plasma proteins. Crossing blood–brain barrier is predicted to be successful for 11 compounds. The created quantitative structure activity relationship model represents an excellent predictive tool and enables determination of pharmacokinetic properties of examined compounds. Docking analysis defined molecules I₃ and II₃ to be the best candidates; however, compound II₃ violates the Lipinski rule. It has been concluded that molecules with hydroxyl group at C‐3 more effectively pass through blood–brain barrier while structures with benzyloxy groups have stronger interactions with CYP1A19. Molecules II₂, II₄, II₆, and II₇ are regarded as most suitable candidates for further investigation considering their good pharmacokinetic and docking characteristics. Copyright © 2017 John Wiley & Sons, Ltd.     

抗感染新药非达霉素的药理作用与临床评价

非达霉素(fidaxomicin)是一种新型的大环内酯类抗生素,适用于艰难梭菌相关性腹泻(clos-tridium difficile-associated diarrhea,CDAD)的治疗。本文参考美国FDA的相关资料,对非达霉素的药理作用、药动学、临床评价、安全性评价及药物相互作用等进行综述。