Table 1.

Model parameter estimates using the ocular-serum TMDD model

Parameter	Symbol (unit)	Estimate	RSE (%)	95% CI		Shrinkage (%)
				Lower	Upper
Ocular parameters
Ocular elimination rate constant of druga	kout (1/day)	0.117	1.25	0.111	0.123
Ocular elimination rate constant of complex	koutC (1/day)	0.135	1.54	0.127	0.144
Ocular influx/synthesis rate constant of target	kinT (µg/mL/day)	0.364	0.635	0.360	0.369
Correction factor for drug:target molar ratio and assay differencesc	λA	2.23	27.7	1.440	3.46
Vitreous volume of distribution	VVITR (mL)	3.09	3.24	2.88	3.23
Ocular degradation/elimination rate constant of drug target	koutT (1/day)	0.27	0.935	0.236	0.276
Vitreous-aqueous partition coefficient of drug	λAQ	13.0	0.586	12.7	13.4
Systemic parameters
Systemic volume of distribution	Vc (mL)	2410	0.0658	2390	2440
Systemic elimination rate constant of druga	k (1/day)	1.89	6.53	1.74	2.05
Quasi-steady rate constantd	Kss (µg/mL)	0.96 × 10−3 (fixed)
Covariates
Power for age effect on kout	Θage-kout	−0.770	45.5	−1.45	−0.0831
Power for age effect on k	Θage-k	−1.63	23.5	−2.38	−0.877
Multiplier for sex effect on k	Θsex-k	0.739	21.1	0.652	0.837
Variability
Intersubject variability for ocular clearance		27.3%	19.1b	21.6%	32.0%	6.3
Intersubject variability for correction factor	ω2λA	59.1%	38.0b	29.8%	78.0%	0.8
Intersubject variability for systemic clearance		27.5%	23.8b	20.1%	33.3%	20.7
Residual error for aqueous measurements	, AQ	25.8%	28.3b	17.2%	32.2%
Residual error for serum measurement	, SER	32.9%	10.1b	29.5%	36.1%

CI, confidence interval; RSE, relative standard error.

^aFor a typical 80-year-old male patient.

^bRSE for variances.

^cRatio of the molecular weights of the drug and the target is equal to 2 (within 95% CI of the estimated value). Minor difference with the estimated value could be due to assay differences or differences in volumes of distributions of the drug and the target.

^dFixed to 20 pM, approximately equal to in vitro KD value (19.7 pM), as the estimated elimination rate of the drug-target complex (k_outC) is much smaller than dissociation rate of the drug-target complex.8,11