Mapping genes for drug chronotherapy

Abstract

Genome-wide association studies have been increasingly used to map and characterize genes that contribute to interindividual variation in drug response. Some studies have integrated the pharmacokinetic (PK) and pharmacodynamic (PD) processes of drug reactions into association mapping, gleaning new insight into how genes determine the dynamic relationship of drug effect and drug dose. Here, we present an evolutionary framework by which two distinct concepts, chronopharmacodynamics and heterochrony (describing variation in the timing and rate of developmental events), are married to comprehend the pharmacogenetic architecture of drug response. The resulting new concept, heterochronopharmacodynamics (HCPD), can better interpret how genes influence drug efficacy and drug toxicity according to the circadian rhythm of the body and changes in drug concentration.

Figure 1

Types of variation in drug response modulated by heteropharmacodynamics (HPD) parameters. (A) High-low variation where one individual has a greater drug effect than the other during the full spectrum of concentration. (B) Fast-slow variation where one individual responds to drug concentration at a greater rate than the other although they starts from the same baseline. (C) Long-short variation where one individual displays an extended spectrum of drug concentration compared to the other. (D) Reverse variation where one individual with a low baseline surpasses its high-baseline counterpart during changing concentrations.

Figure 2

Curves of drug response (A), drug response rate (B), and drug response acceleration (C). Three (x,y)-coordinates on the curves, (C_A, E_A), (C_I, E_I), and (C_D, E_D), are shown, presenting the inflection point, the maximum acceleration and maximum deceleration of drug response curve, respectively.

Figure 3

Genotypic differences in the curve of heart rate response to dobutamine at a QTL. (A) The QTL detected is a single SNP at codon 27 within the β2AR gene. (B) The QTL detected represents haplotype variants composed of two SNPs at codon 16 and 27 within the β2AR gene. Haplotype GG is a key determinant, whose combinations with the rest three haplotypes (collectively expressed by bars) form three composite diplotypes [2]. Genotypic differences in several key heteropharmacodynamic parameters are shown.

Figure 4

The diagrammatic representation of heterochronopharmacodynamics for the same patient administered by a drug at two dosing times, midnight (blue curve) and 6 am (red curve). (A) Drug effect changes as a function of time after administration at different concentrations. (B) Drug effect changes as a function of concentration at different times. Vertical slash lines present the timing of drug response acceleration (1), the timing of drug response inflection point (2), and the timing of drug response deceleration (3). Blue lines and red lines correspond to dosing times at midnight and 6 am, respectively.