Table I.
Empirical Models Which Describe the (Systemic) PK After Oral Drug Inhalation with an Inhalation Device
| Drug | Inhalation device | Trial population | Data | Data analysis methoda | Systemic disposition model | Absorption model | Oral BAb | Safety/efficacy assessment | Model type | Reference |
|---|---|---|---|---|---|---|---|---|---|---|
| Active metabolite of ciclesonide | pMDI | Healthy volunteers, AB patients (adults and pediatrics), patients with liver cirrhosis | Inhalation data | NLME approach | 1 CMT body model | First-order absorption process | Negligible | Safety | I | (61) |
| Active metabolite of ciclesonide | pMDI | Healthy volunteers, AB patients | Inhalation data | NLME approach | 1 CMT body model | First-order absorption process (absorption rate constant could not be estimated and was fixed to a high value) | Negligible | Safety | I | (62) |
| Active metabolite of ciclesonide, fluticasone propionate | pMDI | AB patients | Inhalation data | NLME approach | Ciclesonide metabolite: 2 CMT body model; fluticasone propionate: 1 CMT body model | Ciclesonide metabolite: first-order absorption process, fluticasone propionate: first-order absorption process | Negligible | Safety | I | (63) |
| Albuterol (R) and (S) enantiomer | Nebulizer (PARI LC PLUS®, DURA-NEB® 3000) | 4- to 11-year-old patients with mild to moderate AB | Inhalation data | NLME approach | 2 CMT body model (R), 1 CMT body model (S) | Zero-order absorption process (R and S) | (R): 18%, (S): 68% | n.r. | I | (69) |
| Albuterol (R) and (S) enantiomer | MDI (Proventil®, Schering Corp.) + spacer (Aerochamber™) | Healthy volunteers (males and females) | Inhalation data | 2-stage approach | 2 CMT body model | First-order absorption process | 40–50% | n.r. | I | (68) |
| Amikacin (liposomal) | Pari LC® Star jet™ nebulizer | Cystic fibrosis patients | Inhalation (plasma and urine data) | NLME approach | 1 CMT body model | First-order absorption process | n.r. | Efficacy (correlation between AUC and pulmonary efficacy tested) | I | (98) |
| Budesonide (epimeric), fluticasone propionate | pMDI | Healthy volunteers | Inhalation data | NLME approach (exploratory 2-stage approach) | Budesonide: 1 or 2 CMT body model, fluticas1 propionate: 1 CMT body model | Budesonide: first-order absorption process Fluticasone propionate: first-order absorption process | Budesonide: 10%, fluticasone propionate: 1% | n.r. | I | (64) |
| Budesonide, flunisolide, fluticasone proprionate, triamcinolone acetonide | Not predefined | Healthy volunteers | Inhalation and IV data | Semi-mechanistic empirical modeling | Budesonide, flunisolide, fluticasone propionate: 2 CMT body model, triamcinolone acetonide: one CMT body model | 3 first-order absorption processes (2 for pulmonary absorption, 1 for absorption from the GI tract), also accounting for pulmonary dissolution processes | Budesonide: 11%, flunisolide: 20%, fluticasone proprionate: <1%, triamcinolone acetonide: 23% | n.r. | II | (81) |
| Budesonide/fluticasone propionate | Turbohaler® (budesonide), Diskus® (fluticasone propionate) | Healthy volunteers | Inhalation Data | NLME approach (exploratory 2-stage approach) | Budesonide: 1 CMT body model, fluticasone propionate: 2 CMT body model | Budesonide: first-order absorption process (absorption rate constant fixed to high value), fluticasone propionate: first-order absorption process | Budesonide: 10%, Fluticasone propionate: 1% | Safety | I | (65) |
| Ciprofloxacin | T-326 DPI | Healthy volunteers | Inhalation, IV, and oral data | 2-stage approach | “Previously validated simulated concentration-time profile” | Instantaneous bolus input, absorption from the GI tract CMT (not further specified), additional transit CMT to the GI tract | n.r. | Safety | II-b | (80) |
| Fenoterol | pMDI | AB patients | Oral and nasal inhalation, IV bolus, and IV infusion data | 2-stage approach | 3 CMT body model | First-order absorption process | 1.5% | Safety | I | (94) |
| Fluticasone propionate | DPI (Diskus® dry powder device) | Healthy volunteers | Inhalation data | 2-stage approach | 2 CMT body model | First-order absorption process | Negligible | n.r. | I | (66) |
| Fluticasone Propionate | pMDI attached to AeroChamber Plus® with Facemask or Babyhaler® | 1- to 4-year-old AB patients | Inhalation data | NLME approach | 1 CMT body model | Zero-order absorption process | Negligible (<1%) | n.r. | I | (67) |
| Formoterol | pMDI | Healthy volunteers | Inhalation data | 2-stage approach | 2 CMT body model | 2 first-order absorption processes from GI tract (+lag time) and lung | “Significant” (68)—included in the model | Safety | II | (70) |
| GLP-1 | DPI (MedTone® Inhaler) | Healthy volunteers, DM type 2 patients | Inhalation data | NLME approach | Healthy volunteers: 2 CMT body model, type 2 DM: 1 CMT body model | First-order absorption process | n.r. | Systemic efficacy | I | (75) |
| Glycopyrronium bromide | DPI (Breezhaler® Device) | Healthy volunteers | Inhalation (with and without charcoal treatment) and IV data | NLME approach | 3 CMT body model | 3 first-order pulmonary absorption processes (fastest: instantaneous input), 1 first-order GI tract absorption process | 8.2% | n.r. | II | (59) |
| HMR1031 (VLA-4 antagonist | DPI (Ultrahaler®) | Healthy volunteers (males) | Inhalation data | NLME approach | 1 CMT body model | First-order absorption process | 5% (preclinical data) | n.r. | I | (77) |
| Indacaterol | Single-dose DPI | COPD patients (Asian and Caucasian populations), AB patients | Inhalation data | NLME approach | 2 CMT body model | Instantaneous input | n.r. | n.r. | I | (71) |
| Insulin | Soft mist inhaler (AERx® IDMs), DPI (Spiros™ blisterdisk® inhaler) | DM type 1 patients, healthy volunteers (male and female) | Inhalation and subcutaneous data | Model-based meta-analysis | 1 CMT body model (developed with SC data with assumption: 100% subcutaneous bioavailability) | First-order absorption process | n.r. | Systemic efficacy | I | (41) |
| Insulin/Insulin lispro | Nebulizer, DPI, AERx®, Exubera® | Healthy volunteers (smoker and non-smoker), DM type 1 and type 2 patients | Inhalation and IV data | Model-based meta-analysis | 2 CMT body model (rate constants estimated and volume of distribution fixed to literature value) | First-order absorption and first-order non-absorption loss | n.r. | n.r. | I-b | (42) |
| Insulin (human recombinant DNA origin) | DPI (Model M, Boehringer Ingelheim and Model Alpha, MannKind Corporation) | Healthy volunteers (non-smoking male and female) | Inhalation, subcutaneous and IV data | NLME approach | 2 CMT body model | First-order absorption process | n.r. | n.r. | I | (79) |
| Laninamivir octanoate (prodrug), Laninamivir | “prototype” and “commercial” | Healthy volunteers, adults with renal impairment, patients with influenza virus infection (adult and pediatric) | Inhalation data | NLME approach | Laninamivir octanoate: 2 CMT body model, laninamivir: 1 CMT body model | Laninamivir octanoate: instantaneous input, laninamivir: first-order absorption process | Laninamivir octanoate: 0.3%, Laninamivir: 3.5% | n.r. | I | (74) |
| Morphine | Soft mist inhaler (AERx® system) | Healthy volunteers | Inhalation and IV data (arterial sampling) | NLME approach | 3 CMT body model with lag time for IV dosing | 2 CMT absorption model | 25% | Safety | II | (60) |
| Olodaterol | Soft mist inhaler (Respimat®) | Healthy volunteers | Inhalation and IV data | NLME approach | 3 CMT body model | 3 parallel first-order absorption processes | Negligible | n.r. | II | (57) |
| PF-00610355 | DPI (MIAT) DPI (CRC-749) | Healthy volunteers, AB patients, and COPD patients | Inhalation data | NLME approach | 3 CMT body model | First-order absorption with 1 transit CMT | 28-36%c | n.r. | I-a | (72) |
| Pitrakinra | DPI (RS01 Dry Powder Inhaler-Model 7), Nebulizer (PARI LC® Plus Turbo nebulizer) | AB patients, eczema patients | Inhalation and subcutaneous data | NLME approach | 1 CMT body model | Single-dose: first-order absorption process with lag time, multiple dose: first-order absorption process without lag time | n.r. | Correlation between systemic PK and efficacy tested but not significant | I | (99) |
| Prochlor-perazine | Single-dose delivery system (Staccato® system delivery platform) | Healthy volunteers | Inhalation and IV data | NLME approach | 2 CMT body model | 3 parallel absorption processes with transit CMTs (relevant for both inhalation and IV administration) | Low (78) | n.r. | II-a | (78) |
| Tiotropium | Soft mist inhaler (Respimat®) | Healthy volunteers | Inhalation and IV data (both urine and plasma) | NLME approach | 4 CMT body model (with Michaelis–Menten non-renal elimination and Michaelis–Menten peripheral binding) | 2 parallel first-order absorption processes | Negligible | n.r. | II | (58) |
| Tobramycin | TOBI® Podhaler® | Cystic fibrosis patients | Inhalation data | NLME approach | 2 CMT body model | First-order absorption process | n.r. | n.r. | I | (76) |
| Zanamivir | DPI | Healthy volunteers, influenza-like illness patients | Oral and nasal inhalation data | NLME approach | 1 CMT body model | First-order absorption process | n.r. | n.r. | I | (73) |
AB asthma bronchiale, BA bioavailability, CMT compartment, COPD chronic obstructive pulmonary disease, DM diabetes mellitus, DPI dry powder inhaler, GI gastrointestinal, IV intravenous, NLME nonlinear mixed-effects, n.r. not reported, (p)MDI (pressurized) metered dose inhaler, SC subcutaneous
aSome data evaluations also contained non-compartmental analyses. These approaches are not listed here as they are not part of the review
bValues for oral bioavailability are from the specific publication
cValue not representing oral bioavailability but contribution of the orally absorbed fraction to the total systemic exposure