Dataset Information

Seconds-resolved pharmacokinetic measurements of the chemotherapeutic irinotecan in situ in the living body.

ABSTRACT: The ability to measure drugs in the body rapidly and in real time would advance both our understanding of pharmacokinetics and our ability to optimally dose and deliver pharmacological therapies. To this end, we are developing electrochemical aptamer-based (E-AB) sensors, a seconds-resolved platform technology that, as critical for performing measurements in vivo, is reagentless, reversible, and selective enough to work when placed directly in bodily fluids. Here we describe the development of an E-AB sensor against irinotecan, a member of the camptothecin family of cancer chemotherapeutics, and its adaptation to in vivo sensing. To achieve this we first re-engineered (via truncation) a previously reported DNA aptamer against the camptothecins to support high-gain E-AB signaling. We then co-deposited the modified aptamer with an unstructured, redox-reporter-modified DNA sequence whose output was independent of target concentration, rendering the sensor's signal gain a sufficiently strong function of square-wave frequency to support kinetic-differential-measurement drift correction. The resultant, 200 ?m-diameter, 3 mm-long sensor achieves 20 s-resolved, multi-hour measurements of plasma irinotecan when emplaced in the jugular veins of live rats, thus providing an unprecedentedly high-precision view into the pharmacokinetics of this class of chemotherapeutics.

SUBMITTER: Idili A

PROVIDER: S-EPMC6788505 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Seconds-resolved pharmacokinetic measurements of the chemotherapeutic irinotecan <i>in situ</i> in the living body.

Idili Andrea A Arroyo-Currás Netzahualcóyotl N Ploense Kyle L KL Csordas Andrew T AT Kuwahara Masayasu M Kippin Tod E TE Plaxco Kevin W KW

Chemical science 20190722 35

The ability to measure drugs in the body rapidly and in real time would advance both our understanding of pharmacokinetics and our ability to optimally dose and deliver pharmacological therapies. To this end, we are developing electrochemical aptamer-based (E-AB) sensors, a seconds-resolved platform technology that, as critical for performing measurements <i>in vivo</i>, is reagentless, reversible, and selective enough to work when placed directly in bodily fluids. Here we describe the developme ...[more]

PMID: 31673321

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Project description:BACKGROUND:Drug development considering individual varieties among patients becomes crucial to improve clinical development success rates and save healthcare costs. As a useful tool to predict individual phenomena and correlations among drug characteristics and individual varieties, recently, whole-body physiologically based pharmacokinetic (WB- PBPK) models are getting more attention. WB-PBPK models generally have a lot of drug-related parameters that need to be estimated, and the estimations are difficult because the observed data are limited. Furthermore, parameter estimation in WB-PBPK models may cause overfitting when applying to individual clinical data such as urine/feces drug excretion for each patient in which Cluster Newton Method (CNM) is applicable for parameter estimation. In order to solve this issue, we came up with the idea of constraint-based perturbation analysis of the CNM. The effectiveness of our approach is demonstrated in the case of irinotecan WB-PBPK model using common organ-specific tissue-plasma partition coefficients (Kp) among the patients as constraints in WB-PBPK parameter estimation. RESULTS:We find strong correlations between age, renal clearance and liver functions in irinotecan WB-PBPK model with personalized physiological parameters by observing the distributions of optimized values of strong convergence drug-related parameters using constraint-based perturbation analysis on CNM. The constraint-based perturbation analysis consists of the following three steps: (1) Estimation of all drug-related parameters for each patient; the parameters include organ-specific Kp. (2) Fixing suitable values of Kp for each organ among all patients identically. (3) Re-estimation of all drug-related parameters other than Kp by using the fixed values of Kp as constraints of CNM. CONCLUSIONS:Constraint-based perturbation analysis could yield new findings when using CNM with appropriate constraints. This method is a new technique to find suitable values and important insights that are masked by CNM without constraints.

Dataset Information

Seconds-resolved pharmacokinetic measurements of the chemotherapeutic irinotecan in situ in the living body.

Publications

Seconds-resolved pharmacokinetic measurements of the chemotherapeutic irinotecan <i>in situ</i> in the living body.

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