Table 4.

Characteristics and Results of Studies for Developing PK/PPK Models

Author (Year)	Country	Study Design	Characteristics of Patients Included	Patients with Neutropenia (%)	Sample Size	Number of serum Concentrations	Age	Gender (M/F)	Weight (kg)	Renal Function	Vancomycin Dosing	Timing of Vancomycin Sampling	Pharmacokinetic Modeling Method	Model	Pharmacokinetic Parameters
															V	CL	Ke (h−1)	t1/2 (h)
Pharmacokinetic analysis
Kureishi 199026	Canada	Single-center prospective study	Patients with acute leukemia and had absolute granulocyte below 500/mm3	100%	25	NR	NR	NR	NR	NR	Intermittent infusion; 15 mg/kg q12h	Prior to infusion and at 1 and 3 h post-infusion daily during the first 3 days and every 3 to 7 days thereafter	Equations with two steady-state samples	One-compartment model	0.61 ± 0.21 L/kg	NR	NR	5.6 ± 1.8
Le Normand 199428	France	Single-center prospective study	Patients with hematologic malignancies who were neutropenic (100/mm3)	100%	10	130	36.2 (range: 18–50)	4/6	64.6 ± 10.4	141.2 ± 36.2 mL/min	Intermittent infusion; 1000 mg every 12 h	The first dose: prior to injection, at the end of the infusion, and 11 samples collected until 11 h after the end of the infusion	G-Pharm computer program	Two-compartment model	Vc: 22.9 ± 11.4 L	158 ± 51 mL/min	NR	2.94 ± 0.84
Jarkowski 201127	United states	Single-center prospective study	Acute myeloid leukemia patients receiving vancomycin	NR	25	NR	59.12 ± 16.26	17/8	86.05 ± 19.42	85.72 ± 37.28 mL/min/1.73m2	Intermittent infusion; 1970.00 ± 605.19 mg/d	Three samples: 1 h, 3–8 h, and 8–24 h post-infusion	Maximum a priori Bayesian estimation using Adapt 5	Two-compartment model	Vc: 0.23 L/kg Vss: 0.60 L/kg	0.14 L/h/kg	NR	NR
Ghehi 201320	Iran	Single-center prospective study	Patients with neutropenic fever after HSCT	100%	20	40	29.9 ± 9.5	NR	72.5 ± 15.2 (ABW)	104.7 ± 37.0 mL/min	Intermittent infusion; 31.9 (±10.5) mg/kg/d (69.6%:1g q12h; 17.4%:1g q8h)	First steady-state trough (within 30 minutes prior to the fourth dose), peak concentration, random sample	Equations with two steady-state samples	One-compartment model	0.60 (0.44–0.76) L/kg	0.090 (0.071–0.109) L/h/kg 109.7 (82.7–136) mL/min	0.16 (0.13–0.19)	4.9 (3.8–6.0)
Population pharmacokinetic model
Buelga 200529	Spain	Single-center retrospective study	Adult inpatients with an underlying hematologic malignancy	43.7%	215	1004	51.5 ± 15.9	119/96	64.7 ± 11.3	89.4 ± 39.2 mL/min	Intermittent infusion	Blood sampling was ordered as required clinically	Nonlinear mixed-effect modeling approach (NONMEM)	One-compartment model	CL (L/h): 1.08 × CLCR (Cockcroft and Gault) (L/h); CVCL: 28.16% V (L) =0.98 ×TBW; CVV:37.15%.
Okada 201838	Japan	Single-center retrospective study	Patients undergoing allo-HSCT who received preventive treatment with vancomycin	NR	75	227	49 (range: 17–69)	49/26	59.4 (range: 39.4–104.5)	113 (range: 47–253) mL/min	Intermittent infusion initial dosage of 1 g/12 hours (if the CLCR was >75 mL/min/1.73 m2).	Immediately before ad-ministering vancomycin,1 hour after drug administration and at some other points as necessary	Nonlinear mixed-effect modeling approach (NONMEM)	Two-compartment model	Vc (L)= 39.2 × (TBW/59.4)^0.78; CVVc=14.2% CL (L/h) =4.25 × (CLCR/113)^0.70; CVCL=25.2% Vp (L) =56.1; CVVp=66.9%
Bury 201936	The Netherlands	Retrospective matched cohort study	Intravenous vancomycin therapy for ≥ 2 days and at least one available vancomycin concentration	26.7%	116	742	61.4 ± 13.4	67/49	NR	Median 92.7 mL/min	Intermittent infusion The specific dosing was not pre-specified	NR	Nonlinear mixed-effect modeling (NONMEM)	Two-compartment model	CL(L/h) = 3.22+(1+0.00834 × (CLCR −104)) × 1.277NEUTROPENIA; CVCL=33.0%

Abbreviations: V, volume of distribution; CL, clearance; Ke, elimination rate constant; t_1/2, half-life; NR, not reported; ABW, adjusted body weight; TBW, total body weight; CL_CR, creatinine clearance; Vc, volume of central compartment; Vss, steady-state volume of distribution; Vp, distribution volume of peripheral compartment.