Table 4.

Tacrolimus apparent clearance CL/F association with extrarenal adverse effects: model parameter estimates

Adverse effect: categories			PK predictor	Parameter estimates (95% CI)		OR	P‐valuea
Gastrointestinal
Diarrhea	0	Absence	Tacrolimus CL/F (l h–1)	β 1 = 0.745	(0.019, 0.99)	0.94	<0.02
				α 2 = 1.29	(–2.57, –0.74)
	1	Low		θ CL = –0.059	(–0.093, –0.018)
	2	High
Dyspepsia	0	Absence	Tacrolimus CL/F (l h–1)	β 1 = 0.208	(0.020, 0.69)	1.03	<0.05
	1/2/3	Presence		θ CL = 0.027	(0.0008, 0.065)
Neurological
Insomnia	0	Absence	Tacrolimus CL/F (l h–1)	β 1 = –0.947	(–1.84, –0.18)	0.95	<0.05
	1/2/3	Presence		θ CL = –0.053	(–0.10, –0.019)
Neurological ratios	0	Absence	Tacrolimus CL/F (l h–1)	β 1 = 0.391	(0.109, 1.53)	2.74	<0.05
	>0.14	Presence		θ CL = 1.01	(0.25, 1.91)

PK, pharmacokinetic; CL/F, tacrolimus apparent oral clearance; θ _CL, slope for tacrolimus CL/F effect; OR, odds ratio

The probability p_i of an adverse effect event is defined as follows: $p_i=\frac{e^{\beta +\theta ·X_i}}{1+e^{\beta +\theta ·X_i}}$

For binary adverse effect events (dyspepsia, insomnia, neurological ratios), β ₁ represents the underlying baseline for p(1), the probability of an adverse effect occurring. The probability of an adverse effect not occurring is defined as 1 – p(1)

For ordered categorical variables (diarrhoea), β ₁ represents the underlying baseline for p(1), the sum of β ₁ and α ₂ represents the underlying baseline p(2). The probability of an adverse effect grade 2 occurring is p(2). The probability of an adverse effect grade 1 occurring is p(1) – p(2). The probability of an adverse effect not occurring (grade 0) is 1 – p(1)

Neurological adverse effect ratio represents a composite of individual rated adverse effects: tremors, headaches, insomnia 17, 18

^aThe P‐value indicated the statistical significance of the exposure metric on the adverse effect model developed in NONMEM. The exposure metric was considered as significant if it showed a decrease of at least 3.84 points (χ²‐test, P < 0.05) in the objective function value from the initial logistic model

The odds of interest increases by e^θCL fold for every one unit increase in tacrolimus CL/F