### Introduction

### Materials and Methods

### Drug administration

### Neuromuscular monitoring

_{start}is the first T1% value after calibration and T1%

_{end}is the T1% value at complete recovery. Corrected T1% was T1% multiplied by F. Corrected T1% values were obtained only for the recovery phase.

### Biophase concentration

### Interaction model

*e*

_{r}and C

*e*

_{c}are the effect site concentrations of rocuronium and cisatracurium, respectively, C

*e*

_{50,r}and C

*e*

_{50,c}are the effect site concentrations of rocuronium and cisatracurium that produce 50% maximal effects, respectively, and α is the interaction coefficient. When α > 0, the drug interaction is synergistic; when α < 0, the drug interaction is antagonistic; and when α = 0, the drug interaction is additive. A larger positive α indicates stronger synergy. To assess the significance of α, we investigated whether the 95% confidence interval of α included 0 or not.

_{max}model for both TOF ratio and T1%:

*E*

_{0}is the effect when no drug is given,

*E*

_{max}is the maximal effect of a drug combination, and γ is the dose response curve slope.

*e*

_{50}for each drug, C

*e*

_{50,r}and C

*e*

_{50,c}are the effect site concentrations of rocuronium and cisatracurium that produce 50% of maximal effects, respectively.

_{50}(θ) is the normalized unit of concentration that produces 50% of the maximal effect at a ratio of θ.

*E*

_{0}is the baseline effect with no drug,

*E*

_{max}(θ) is the maximum possible drug effect at ratio θ, and δ(θ) is the steepness of concentration-response relationship at ratio θ. Each drug ratio can have its own U

_{50}and δ, and hence each of the ratios behaves as a single drug with its own sigmoidal concentration–response relationship. However, in this study,

*E*

_{max}was fixed at 0 at all θ ratios and δ was assumed to be identical at all ratios.

_{50}(θ), second-order polynomial functions were implemented:

_{50}(θ) at each θ ratio. Additivity of the interaction can also be defined with β. That is, when β > 0, the drug interaction is synergistic; when β < 0, the drug interaction is antagonistic; and when β = 0, the drug interaction is additive [13].

#### Parameter estimation

### Results

_{50}(θ) values of TOF ratio and T1% measurements were positive in the range 0 < θ < 1 and showed an upward concave plot of < 1, which means that the drugs acted synergistically (Fig. 2).

### Discussion

_{50}and δ values. Based on this assumption, U

_{50}could be presented as a function of combination ratio as shown in Fig. 2. At ratios of 0 and 1, U

_{50}(θ) should be 1, and between ratios 0 and 1, it should be less than or greater than 1. Theoretically, additivity is defined as a U

_{50}(θ) value of 1. However, a 10% degree of deviation in measurement of the parameters should be taken into consideration; hence, the additive interaction was considered to exist when U

_{50}(θ) was between 0.9 and 1.1 [13,14]. In the current Minto model, the θ ratio, which corresponds to U

_{50}(θ) < 0.9, is between the ratio 0.17 and 0.83 for the TOF ratio model and between the ratio 0.15 and 0.85 for the T1% model (Fig. 2). It is important that the θ ratio should not be misunderstood as the ratio of the amount of intravenously administered doses. The θ ratio is the predicted concentration ratio of the two drugs at the effect site regardless of the ratio of the amount of intravenously administered doses.