TABLE 14

Compilation of challenging experimental situations for DRT data analyses

ChallengeMain ProblemPotential SolutionReason for Cautious Application of DRTReference
Endogenous agonistsNo systemic exposure to test compoundMultiple input routes and rates may reveal the relative biophase availabilityDifficult to discriminate between endogenous and exogenous contribution to PDAndersson et al. (2017)
Time-varying baselineImpact of potential endogenous agonist(s)Dose-range finding studies including the zero doseNo exposure data on endogenous agonist(s)Lalonde et al. (1999)
Combination therapiesNo systemic exposure of the individual drugsSystematic dose-range finding (including zero dose, different routes, rates, and modes) design is lackingIf individual potencies need to be established, the contribution has to be based on exposure measuresGruwez et al. (2005, 2007)
Multiple target sitesThe contribution of each target difficult to assess if exposure measures are not knownMultiple agonist and antagonist dose levels may be appliedIf multiple agonist and antagonist dose levels are not availableAndersson et al. (2017)
Synergistic systemsNo systemic exposure of the individual drugsSystematic dose-range finding (including zero dose, different routes, rates, and modes) design is lackingWhen a systematic dose-range finding (including zero dose) design is lackingWilbaux et al. (2015)
Safety studiesExposure to test compound not known and is needed for safety assessmentSystematic dose-range finding (including zero dose, different routes, rates, and modes) design is lackingDifficult to assess safety margin without exposure measures or biomarkerAhn et al. (2014)
Oligonucleotide kineticsExtreme disposition patterns in plasmaSystematic dose-range finding (including zero dose, different routes, rates, and modes) design is lacking. Use of exposure-response model (e.g., PBPK) as one building blockWhen a systematic dose-range finding (including zero dose) design is lacking
Time-dependent changes in disposition or target parametersExposure to test compound not knownSystematic dose-range finding (including zero dose, different routes, rates, and modes) design is lackingWhen a systematic dose-range finding (including zero dose and repeated dose) design is lackingAndersson et al. (2017)
Iontophoretic systemsExact drug dose and input rates are seldom knownDose-range finding studies including the zero dose, current ranging studies (see Liu et al., 2016, for alternative design)When a systematic dose-range finding (including zero dose) design is lackingLiu et al. (2016)
  • PBPK, physiologically based pharmacokinetic; PD, pharmacodynamics.