A Review of Population Pharmacokinetic Models of Posaconazole

Figures & data

Table 1 Population Characteristics of the Studies Included in the Review

Study	Year	Country	Study Design	N(Male/Female)	Age(Year)^a	Body Weight(kg)^a	Subject Characteristic	Routes	Dose(mg)	Assay
M1^Citation23	2010	Germany	Single, P	32 (16/16)	49.5 (17–66)	68.5 (49–115)	Adults, SCT recipients with hematological malignancies	PO	NA	HPLC
M2^Citation24	2010	USA	Multi, P	215 (117/98)	52	70	Adults & pediatrics, neutropenic patients receiving chemotherapy for AML/MDS	PO	200 tid	LC-MS/MS
M3^Citation25	2012	Germany	Single, P	84 (42/42)	55 (19–73)	77.7 (48.0–119.2)	Adults, patients with AML/MDS	PO	200 tid	HPLC
M4^Citation26	2012	Germany	Single, P	15 (6/9)	58 (41–79)	NA	Adults, patients in a SICU	Nasogastric Tube	200 q6h	HPLC
M5^Citation18	2014	Australia, Netherlands	Multi, R	102 (58/44)	Study1: 38 (18–54) Study2: 50 (18–79)	Study1: 74 (44–104) Study2: 71(38–122)	Adults, healthy volunteers(study1) and patients(study2)^b	PO	Study1: 200–800 Study2: 160–1200^c	HPLC
M6^Citation27	2017	France	Single, P	49 (29/20)	53 (19–73)	72 (50–125)	Adults, hematological malignancies	PO	Day1: 300 bid, Maintenance: 300 qd	LC-MS/MS
M7^Citation28	2018	USA	Multi, P	335 (205/130)	Study1:31.4±7.1 Study2:36.0±11.9 Study3:38.2±7.3 Study4:37.7±9.8 Study5:45.8±9.0 Study6:51.0±14.0	Study1:74.3±10.0 Study2:76.1±14.7 Study3:79.6±13.9 Study4:76.8±12.0 Study5:73.9±11.3 Study6:77.1±17.7	Adults, healthy volunteers(study1, study2, study3, study4, study5) and patients(study6)^d	PO	Study1:100^e Study2:300^f Study3:400^e Study4:100^e Study5:200, 400^f Study6:200, 300^g	NA
M8^Citation29	2019	UK	Single, R	117 (43/74)	5.7 (0.5–18.5)	17.8 (6.05–74.8)	Infants & Children, immunocompromised	PO	200 (32–630)^a	NA
M9^Citation30	2020	Netherlands	Multi, P	24 (12/12)	Normal(300mg IV): 22(20–37); Obese(300mg IV): 51 (31–63); Obese(400mg IV): 37.5 (25–50)	Normal(300mg IV):72.3 (61.4–85.4) Obese(300mg IV): 129 (109–190) Obese(400mg IV): 144 (107–175)	Adults, obese and non-obese healthy volunteers	IV	Obese:300/400 Normal:300	UPLC
M10^Citation31	2021	Spain	Single, P	36 (17/19)	53 (27–73)	68.3 (40.0–103.5)	Adults, SCT recipients	PO	Day1: 300 bid, Maintenance: 300 qd	UPLC
M11^Citation32	2021	UK	Single, R	37 (13/24)	14 (7–17)	45.55 (25–82.8) Age 6–11 years: 31.5(25–58) Age 12–17 years: 50(34.7–82.8)	Pediatrics, cystic fibrosis	PO	300(100–600) Age 6–11 years: 300(100–300)^a Age 12–17 years: 300(200–600)^a	2D HPLC-MS/MS
M12^Citation33	2021	Romania	Multi, P	14 (5/9)	6.7 ± 2.8	19.9 ± 6.1	Pediatrics, hematologic malignancies	PO	100 (77.3–100)^a, tid	HPLC
M13^Citation34	2021	Belgium, Netherlands, France	Multi, P	6 (3/3)	44 (40–57)	76 (67–97)	Adults, critically ill patients during ECMO	IV	Day1: 300 q12h, Day2: 300 q24h, with an infusion duration of 90min	HPLC

Notes: ^aValues are expressed as median (range), mean (range) or mean ± standard deviation. ^bPatients with underlying condition: AML; Acute lymphoblastic leukemia; Non-Hodgkin’s lymphoma; MDS; Multiple myeloma; Diabetes mellitus type 2; Chronic lymphocytic leukemia; Myelofibrosis; Hodgkin’s lymphoma; acute biphenotypic leukemia; gray-zone lymphoma; T-polylymphocytic leukemia; chronic myeloid leukemia; aplastic anemia; HIV positivity; rheumatoid arthritis; Crohn’s disease; and none (Histoplasma). ^cHealthy volunteers: day 1, 200 mg; day 2, 200 mg twice daily; days 3–10, 400 mg twice daily; Patients: multiple dosing:160–1200 mg total daily dose. ^dPatients with the following primary diagnosis at study entry: AML; GVHD, graft-versus-host disease (the subjects underwent allogeneic hematopoietic stem cell transplantation); MDS. ^eSingle dose. ^fSingle or multiple doses. ^gMultiple doses.

Abbreviations: Multi, Multicenter; P, prospective; R, retrospective; NA, not available; SCT, allogeneic stem cell transplant; AML, acute myelogenous leukemia; MDS, myelodysplastic syndrome; ECMO, extracorporeal membrane oxygenation; SICU, Surgical Intensive Care Unit; PO, oral administration; IV, intravenous administration; HPLC, high-performance liquid chromatography; LC-MS/MS, liquid chromatography–tandem mass spectrometry; UPLC, ultra-high-performance liquid chromatography; 2D HPLC-MS/MS, 2D TurboFlow high-performance liquid chromatography-tandem mass spectrometry.

Figure 1 Flow chart of the article selection process.

Table 2 Model Characteristics of the Studies Included in the Review

Study	Samples		Modelling				Simulation
	Total	Per Subject	Data	Software, Algorithm	P value(Forward /Backward)	Validation	Optimal Dosing Regimen	Target (mg/L)
M1^Citation23	149	5(1–12)	Sparse data from a TDM study	NONMEM, FOCE-I	0.05/NA	GOF, modified jackknife evaluation	NA	NA
M2^Citation24	702	3–5	Sparse data from a multicenter PK study	NONMEM, FOCE	NA/NA	Bootstrap	NA	NA
M3^Citation25	643	5 (1–22)	Sparse data from a TDM study	NONMEM, NA	0.05/0.05	VPC, GOF, modified jackknife evaluation	NA	NA
M4^Citation26	270	18	Rich data from a study	NONMEM, FOCE-I	NA/NA	GOF	NA	NA
M5^Citation18	905	Healthy volunteers:11 Patients:1	Rich data from a PK study; sparse data from an observational study of TDM	NONMEM, FOCE-I	0.005/0.001	pvcVPCs, bootstrap	NA	Prophylaxis: Cmin >0.7
M6^Citation27	205	4.2	Sparse data from a study	Monolix, NA	NA/NA	GOF, NPDE, VPC	Prophylaxis Cmin≥1.5mg/L at 48h or day 7 or 8, reduction of the dose from 300 mg to 200mg	Prophylaxis: Cmin≥0.7, Treatment: Cmin≥1.0 at 48h and at day 10
M7^Citation28	5756	17.6	Rich data from five Phase I study; Sparse data from a Phase III study	NONMEM, FOCE	0.01/0.001	Diagnostic plot, VPC, bootstrap	Day1 300mg twice daily, followed by 300mg/d for maximum of 27 days	Cmin and Cavg >0.5
M8^Citation29	338	3(1–11)	Sparse data from a TDM study	NONMEM, FOCE-I	0.05/0.01	Diagnostic plot, VPC, bootstrap	NA	Prophylaxis: Cmin, ss≥0.7 Treatment: Cmin, ss ≥1.0
M9^Citation30	226	10	Rich data from a multicenter PK study	NONMEM, FOCE-I	0.05/0.01	pcVPC	Treatment WT < 140 kg:300mg/d; WT 140–190 kg: 400mg/d; WT > 190 kg: 500mg/d Prophylaxis WT <190 kg: 300mg/d	Prophylaxis: Cmin≥0.7; Cavg≥0.5 Treatment: Cmin≥1.0; Cavg≥3.75
M10^Citation31	55	1.5	Sparse data from a TDM study	NONMEM, FOCE-I	0.05/0.01	VPC, bootstrap	NA	AUC/MIC^a≥200
M11^Citation32	100	2(1/9)	Sparse data from a TDM study	NONMEM, FOCE-I	0.05/0.01	GOF, VPC, bootstrap	Aged 6–11 years: 300mg q12h for two doses (loading), then 300mg qd; Aged 12–17 years: 400mg q12h for two doses then 400mg qd	Cmin≥1.0 AUC≥30 mg·h/L
M12^Citation33	112	8	Rich data from a multicenter PK study	NONMEM, FOCE-I	0.01/0.001	pcVPC, bootstrap	NA	Ctrough,ss ≥0.7, Cavg,ss:0.5–2.5; population geometric mean Ctrough,ss≥1.0, Cavg,ss≥1.2
M13^Citation34	83	13	Rich data from a multicenter study	NONMEM, NA	NA/NA	GOF, VPC	NA	Prophylaxis: Cmin≥0.7 Treatment: Cmin≥1.0

Notes: ^aMIC=0.06 mg/L for Candida albicans, Candida dubliniensis, Candida parapsilosis and Candida tropicalis; MIC=0.25 mg/L for Aspergillus fumigatus and Aspergillus terreus; MIC=0.5 mg/L for Aspergillus flavus, Aspergillus nidulans and Aspergillus niger.

Abbreviations: TDM, therapeutic drug monitoring; PK, pharmacokinetic; FOCE, first-order conditional estimation; FOCE-I, first-order conditional estimation method with interaction; NA, not available; GOF, Goodness-of-fit plots; VPC, visual predictive check; pcVPC, prediction-corrected visual predictive check; pvcVPCs, prediction-and variability-corrected visual predictive checks; NPDE, normalized prediction distribution errors; WT, body weight; C_min, trough concentration; C_avg, average blood concentration; C_trough,ss, total posaconazole trough concentration at steady-state; C_avg,ss, average concentrations at the steady-state; AUC, area under the concentration–time curve; MIC, minimum inhibitory concentration.

Table 3 Results from Published Population Pharmacokinetic Models of Posaconazole

Study	Structural Model	Pharmacokinetic Parameters	Model Variability			Covariates Excluded	Covariates Retained
			IIV	IOV	Residual Variability
M1^Citation23	1-Compartment model with first-order absorption and first-order elimination	CL/F=67×θDi^diarrhea* L/h V/F=[2250-(AGE-49)×θAGE]×θDi^diarrhea* L Ka=0.4 h^−1(fixed)	CL/F: 26.9%	NA	42%	WT, HT, SEX, fever, daily dose of posaconazole, ethnicity(Caucasian/ other), stem cell transplantation, coadministration of chemotherapy, ranitidine, pantoprazole, cyclosporine, or tacrolimus, fever, GGT levels	CL/F: diarrhea V/F: diarrhea, AGE
M2^Citation24	1-Compartment model	CL/F =65.1 L/h V/F = 3290×1.5^diarrhea* ×1.43^PPI*× 1.84^bilirbin* ×1.17^GGT* ×0.79^race* L Ka=0.0396 h^−1 Ke=0.0198 h^−1	V/F: 15.6% Ke: 2.21%	NA	1.03%	IFIPP/IFIPPP, SEX, AGE, WT, BSA, mucositis, neutropenia, vomiting, H2-receptor antagonist, AST, ALT	V/F: Race (non-white vs white), diarrhea, PPI, bilirubin levels ≥2× ULN, GGT levels ≥2×ULN
M3^Citation25	1-Compartment model with first-order absorption and first-order elimination	CL/F=42.5×θPPI^PPI*×θDi^diarrhea* L/h V/F=[2770+(WT-78)×θWT]×θCHEM^CHEM* L Ka=0.4 h^−1(fixed)	CL/F: 25.3%	NA	23.2%	AGE, HT, SEX, fever, daily dose of posaconazole, ethnicity (Caucasian/other), ranitidine, fever, GGT levels, number of leucocytes in blood	CL/F: diarrhea, PPI V/F: chemotherapy, WT
M4^Citation26	1-Compartment model	CL/F=195 L/h V/F=5280 L Ka=0.77 h^−1	CL/F: 51.8% V/F: 52.0%	CL/F: 48.4% V/F: 21.1%	11.6% 2.8%	WT, HT, BMI, SEX, AGE, albumin, GGT, glutamine-oxalacetic transaminase, glutamatepyruvate transaminase, bilirubin	NA
M5^Citation18	1-Compartment model with first-order absorption with a lag time, and first-order elimination	CL/F=30.2×7.21^PHE*×7.21^RIF*×1.342^FOS*L/h V/F=1100 L Ka=1.26 h^−1 Tlag=1.79 h F=0.549^PPI*×0.655^MET*×2.29^NUT*×0.423^MUC*×0.549^diarrhea*	CL/F: 46.4% V/F: 30.2% Ka: 53.4%	F: 23.6%	6.76% (study1) 53.8% (study2)	WT, AGE, SEX, ranitidine	CL/F:phenytoin, rifampin, fosamprenavir F:PPI, metoclopramide, nutritional supplement, mucositis, diarrhea
M6^Citation27	1-Compartment model with first-order absorption and first-order elimination	CL/F=7.3 L/h V/F=420 L Ka=0.588h^−1(fixed)	CL/F: 24.2% V/F: 28.2%	CL/F: 31.9%	14.8%	AGE, WT, BMI, ALT, AST, ALK, GGT, SEX, bilirubin, disease	NA
M7^Citation28	1-Compartment model with Sequential zero first-order absorption and first-order elimination	CL/F=9.70 L/h V/F=393 L Ka=0.853 h^−1 D1=2.54 h WT on F1: −1.03 Tablet A/B on F1: 0.247 AML/MDS on F1: −0.165 Dosing regimen on CL: 0.750 Food on ka: 0.530	CL/F: 37.9% Ka: 57.5% F1: 24.2%	Ka: 71.1% D1: 48.6% F1: 21.4%	0.42 (phase1 study) 0.322 (phase3 study)	AGE, SEX, BMI, CLcr, race, diarrhea	CL/F: dosing regimen (single dose, multiple dose) Ka: food status relative F(F1): WT, disease state (AML/MDS), tablet formulation (A/B vs C/D)
M8^Citation29	1-Compartment model with first-order absorption	CL/F = 14.95×(WT/70)^0.75 L/h V/F=201.7×(WT/70) L βdose = 99 mg/m^2(fixed) If FORM=1(suspension) Ka =0.588× (WT/70)^−0.25 h^−1(fixed) F=1 If FORM=2(tablet) Ka =0.197× (WT/70)^−0.25 h^−1(fixed) F= [1 - D/(D + βdose)] × 0.67^diarrhea*×0.58^PPI*	CL/F: 63%	NA	47.29% 0.02mg/L	treatment/prophylaxis, macrolides, echinocandins, terbinafine, ciclosporin, tacrolimus, mycophenolate, rifamycin, carbamazepine, phenytoin, histamine H2-receptor antagonists, valaciclovir	CL/F: WT V/F: WT F: diarrhea, PPI
M9^Citation30	2-Compartment model with first-order elimination	CL = 5.83×(TBW/70)^0.54 L/h Q=60.3 L/h V1= 150×(TBW/70)^0.77 L V2 = 96.2×(TBW/70)^1.16 L	V1: 29.5%	NA	16.4%	LBW, BMI, BSA, IBW, AGE, SEX	CL: TBW V1: TBW V2: TBW
M10^Citation31	1-Compartment model with Sequential zero first-order absorption and first-order elimination	CL/F=8.02×0.613^SEX*× (PROT/6.4)^−1.48 L/h V/F=548 L Ka=0.795 h^−1(fixed) D1=2.62 h (fixed)	CL: 28.9% V: 52.4%	NA	21.6%	TBW, BMI, BSA, bilirubin, ALK, AST, ALT, GGT, AGE, eGFR, albumin, ANC, hemoglobin, diagnosis, time since allogeneic transplant, hepatic, digestive GVHD status	CL/F: SEX, PROT
M11^Citation32	1-Compartment model	CL/F=8.43 L/h V/F=186 L Ka=0.16 h^−1	CL/F: 38%	NA	36% 0.15 mg/L	Liver function: ALT, ALK, AST, GGT, bilirubin. potential interacting medicines that were identified in patients included in the dataset: Orkambi(lumacaftor/ivacaftor), rifampicin, rifabutin, clarithromycin, histamine H2-receptor antagonists, PPI	NA
M12^Citation33	1-Compartment model with first-order absorption with a lag time, and linear elimination	CL/F = 15.4×(WT/70)^0.75 L/h V/F = 1150×(WT/70) L Ka = 0.325× (WT/70)^0.25 h^−1 Tlag = 2.71h βdose = 99.1mg/m^2(fixed) F= [1 - D/(D + βdose)] × 0.67^diarrhea*×0.58^PPI*	CL/F: 87.8%	NA	11%	NA	CL/F: WT V/F: WT Ka: WT F: PPI, diarrhea
M13^Citation34	2-Compartment model with first-order elimination	CL=7.7 L/h Q=128 L/h V1=26.2 L V2=396 L	CL: 21.8% V2: 23.4%	NA	1.79%	NA	NA

Notes: *Diarrhea/ PPI/CHEM/PHE/RIF/FOS/MET/NUT/MUC =0 in the absence of this covariate, diarrhea/ PPI =1 in the presence of this covariate; bilirubin=0 if the bilirubin levels<2×ULN, bilirubin=1 if the bilirubin levels≥2×ULN; GGT=0 if the GGT levels<2×ULN, GGT=1 if the GGT levels≥2× ULN; race=0 if the patient is nonwhite, race=1 if the patient is white; SEX=0 for men and SEX=1 for women.

Abbreviations: IIV, inter-individual variability; IOV, inter-occasion variability; CL, clearance; Q, intercompartmental clearance; V₁, central volume of distribution; V₂, peripheral volume of distribution; TBW, total body weight; PROP, proportional; LBW, lean body weight; BMI, body mass index; BSA, body surface area; IBW, ideal body weight; AGE, age; SEX, sex; CL/F, apparent oral clearance from whole blood; V/F, apparent oral volume of distribution in whole blood; β_dose, estimated dose in mg/m² for suspension bioavailability to drop to half that of the tablet; K_a, absorption rate constant; WT, weight; PPI, proton pump inhibitor; ADD, addictive; FORM, formulation; F, bioavailability; D1, duration of zero-order absorption into depot compartment; F1, relative bioavailability; AML, acute myelogenous leukemia; MDS, myelodysplastic syndrome; CLcr, creatinine clearance; HSCT, hematopoietic stem cell transplantation; PHE, phenytoin; RIF, rifampin; FOS, fosamprenavir; MET, metoclopramide; NUT, nutritional supplement; MUC, mucositis; Tlag, absorption lag time; ULN, upper limit of normal; GGT, gamma-glutamyl transferase; IFIPP, proven or probable invasive fungal infection; IFIPPP, proven, probable, or possible invasive fungal infection; ALT, alanine aminotransferase; AST, aspartate aminotransferase; K_e, elimination rate constant; ALK, alkaline phosphatase; PROT, total proteins; eGFR, epidermal growth factor receptor; GVHD, disease of graft versus host disease; CHEM, co-administration of chemotherapy; HT, height.

Figure 2 Simulated steady-state concentration-time profiles at different covariate levels for the reported PopPK models. (A) oral suspension; (B) tablets and intravenous formulations. The dashed line corresponds to a plasma steady state concentration of 0.7 mg/L, and the dash-dotted line corresponds to a plasma steady state concentration of 1.0 mg/L.

Abbreviations: PPI, proton pump inhibitor; GGT, gamma-glutamyl transferase; NUT, nutritional supplements.

Figure 3 Simulated steady-state concentration-time profiles at different dosing regimens for the reported PopPK models. (A) adults or pediatrics receive posaconazole oral suspension 200, 300, and 400 mg thrice daily; (B) adults or pediatrics receive tablets or intravenous formulations of 200, 300, and 400 mg twice daily on the first day and once daily for maintenance. The dashed line corresponds to a plasma steady state concentration of 0.7 mg/L, and the dash-dotted line corresponds to a plasma steady state concentration of 1.0 mg/L.

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