Table 3.

Summary of association of tacrolimus exposure metrics with extrarenal adverse effects: model parameter estimates

Adverse effect: categories			PK predictor	Parameter estimates (95% CI)		OR	P‐value†
Gastrointestinal
Diarrhoea	0	Absence	Dose‐normalized AUCss0–12h (ng h ml–1 mg–1)	β 1 = –2	(–2.97, –0.86)	1.03	<0.05
	1	Low		α 2 = –1.28	(–1.92, –0.68)
	2	High		θ AUCN = 0.027	(0.003, 0.05)
Dyspepsia	0	Absence	Dose‐normalized AUCss0–12h (ng h ml–1 mg–1)	β 1 = 1.73	(0.69, 2.77)	0.96	< 0.05
	1/2/3	Presence		θ AUCN = –0.032	(–0.063, –0.005)
Neurological
Insomnia	0	Absence	Dose‐normalized AUCss0–12h (ng h ml–1 mg –1)	β 1 = –1.21	(–1.92, –0.52)	1.02	< 0.05
	1/2/3	Presence		θ AUCN = 0.024	(0.004, 0.04)
Neurological ratios	0	Absence	Dose‐normalized AUCss0–12h (ng h·ml–1 mg–1)	β 1 = –0.18	(–0.97, –0.04)	1.03	< 0.005
	0.14	Low		α 2 = –1.5	(–1.96, –0.97)
	>0.28	High		θ AUCN = 0.027	(0.02, 0.05)
Cosmetic
Skin changes	0	Absence	Dose‐normalized CMAX (ng ml–1 mg–1)	β 1 = –3	(–3.94, –1.76)	1.23	< 0.02
	1/2/3	Presence		θ CmaxN = 0.208	(0.02, 0.32)
Acne	0	Absence	Dose‐normalized CMAX (ng ml–1 mg–1)	β 1 = –3.24	(–3.92, –1.78)	1.22	< 0.05
	1	Low		α 2 = –1.86	(–2.93, –1.15)
	2	High		θ CmaxN = 0.201	(0.03, 0.3)

PK, pharmacokinetic; AUC_ss0–12h, tacrolimus area under the concentration curve at steady‐state between 0 and 12 h; CL/F, tacrolimus apparent oral clearance; θ _CL, slope for tacrolimus CL/F effect; OR, odds ratio

θ _AUCN slope for AUCss0‐12 h dose‐normalized effect; C_MAX maximum tacrolimus concentration;

θ _CmaxN slope for dose‐normalized C_MAX effect

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, skin changes, insomnia), 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, acne, neurological ratios), 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

The odds of interest increase by e^θAUCN or e^θCmaxN fold for every one unit increase in dose‐normalized AUC or maximum concentration. ^†The P‐value indicates the statistical significance of the PK predictor on the adverse effect model developed in NONMEM. The PK predictor 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