Research Progress of Population Pharmacokinetic of Metformin

Table 3

Details of the covariate building process.

Study	Tested covariate	Covariate selection method	Statistical level for selecting significant covariate (p value)	IIV		RV
				Type	Value	Type	Value
2006 Charles [28]	Age, weight	(1) Forward stepwise inclusion; (2) Backward elimination	(1) p <0.01	CL/F: Logarithmic	17.1%	Additive	SD =0.32 mg/L
2008 Hong [25]	Age, weight, CLCR	Univariate analysis	p <0.01	Exponential	23.0%	Additive	209 ng/mL
2012 Jung-woo [18]	Gender, age, height, weight, CLCR, total bilirubin, haemoglobin	Forward stepwise inclusion	p <0.01	Additive	27.9%	Additive	23.1 ng/mL
2013 Yoon [22]	Weight, age, BSA, ALT,; AST, ALP CLCR	(1) Forward stepwise inclusion; (2) Backward elimination	(1) p <0.05; (2) p <0.01	Exponential		Proportional
2013 Duong [19]	TBW, CLCR, LBW,57 single-nucleotide polymorphisms (SNPs) of metformin transporters (OCT1, OCT2, OCT3, MATE1 and PMAT)	(1) Forward stepwise inclusion; (2) Backward elimination	(1) p <0.05; (2) p <0.01	Exponential	34.1%	Combined	NA
2014 Goswami [20]	SNPs	Stepwise covariate analysis	p <0.01	NA	50%	Combined	NA
2016 Chitnis [26]	Race, metformin country source; Body weight, sex, and age	(1) Forward selection using likelihood ratio test; (2) Backward elimination	(1) α =0.05; (2) α =0.01	Combined	22.5%	Additive proportional
2016 Sam [23]	Age, body weight, height, body mass index, sex, race, ethnicity, genotype group and so on	(1) Univariate analysis; (2) Stepwise backward deletion	(2) p <0.001	Exponential		Additive
2018 Choi [21]	Age, weight,; Height, and creatinine clearance	(1) Forward selected using likelihood-ratio tests; (2) Backward elimination	p <0.05	Combined	19.6%	Proportional
2020 Ling [24]	Weight, BMI, age, eGFR and the genotype of the transporters	(1) Forward stepwise inclusion; (2) Backward elimination	(1) p <0.05; (2) p <0.01	Exponential	16.25%	Exponential	34.64%

Body surface area (BSA), creatinine clearance (CL_CR), liver function [alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP)]; Total body weight (TBW), lean body weight (LBW), SNPs: Single-nucleotide polymorphisms (SNPs).