Table 10. The different consequences of applying models for time-varying covariates, and potential implications for therapy.

Situation	Potential implications for therapy	Examplea
Significant improvementb
1 θBCOV≈0cθDCOV ≠ 0	DCOV superior to COV and BCOV for therapeutic decisions.	Paclitaxel PD, Slope∼BIL
2 θBCOV ≠ 0θDCOV≈0c	BCOV superior to COV and DCOV for therapeutic decisions.	Pefloxacin, CL∼BIL
3 θBCOV ≠ 0θDCOV ≠ 0θBCOV ≠ θDCOV	Both BCOV and DCOV useful, but changes within a patient may require larger (|θBCOV | < |θDCOV|) or smaller (|θBCOV | > |θDCOV|) dosage alterations than between patients.	Gentamicin, CL∼CLC
4 ωCOV, P >0	At baseline, assume no IIV in covariate relationship. Benefit from individualization is related to both ηCOV, P and ηP.At later occasions, DCOV determines therapy, however, changes may have a greater risk of over-/under-dosing therefore more frequent monitoring may be needed.	Pefloxacin, CL∼CLCVoriconazole,CL∼log(ALT)CL∼log(DALKP) Paclitaxel PD, Slope∼DBIL
No significant improvementb
5 θBCOV≈0c	No difference between basing therapy decisions on COV or DCOV, but BCOV is of no value.	Voriconazole, CL∼log(ALKP)
6 θDCOV≈0c	No difference between basing therapy decisions on COV or BCOV, but DCOV is of no value.	Gentamicin, V1∼BSAPefloxacin, CL∼WT
7 θBCOV≈θDCOV	No indication that therapeutic decisions based on BCOV and DCOV should be different.	Gentamicin, V1∼ALBVoriconazole, CL∼ALTPaclitaxel PD, MTT∼BIL
8 ωCOV, P≈0c	Decisions can be based on the assumption that the covariate relationship is the same in all patients.	All examples apart from those in Situation 4

^aExamples from this work, not implying that the models are clinically significant for these drugs.

^bBased on the difference in OFV from the standard covariate model, P < 0.01.

^cThe confidence interval based on the standard error of the parameter estimate encompasses zero.