Practical Recommendations for the Manipulation of Kinase Inhibitor Formulations to Age-Appropriate Dosage Forms
Abstract
:1. Introduction
2. Methods
2.1. Literature Analysis
2.2. Providing Practical Recommendations
3. Results
3.1. Phase I/II Study Results
3.2. LoE 1 Recommendation (Larotrectinib, Dasatinib, Imatinib, Ruxolitnib)
3.3. LoE 2 Recommendation (Sunitinib)
3.4. LoE 3 Recommendation
3.5. LoE 4 Recommendation (Dabrafenib, Bosutinib, Crizotinib, Trametinib)
3.5.1. Dabrafenib and Trametinib
3.5.2. Bosutinib
3.5.3. Crizotinib
3.6. LoE 5 Recommendations (Cobimetinib, Ruxolitinib, Cabozantinib, Dabrafenib, Imatinib, Ponatinib, Bosutinib, Crizotinib, Entrectinib, Nilotinib, Selumetinib, Trametinib)
3.7. BCS Class I: Cobimetinib and Ruxolitinib
3.7.1. Cobimetinib
3.7.2. Ruxolitinib
3.8. BCS Class II and IV
3.8.1. Trametinib
3.8.2. Ponatinib and Imatinib
4. Relevant Additional Recommendations
4.1. Therapeutic Drug Monitoring
4.2. Administration Via Enteral Feeding Tube
5. The Decision Tool
6. Discussion
7. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Terms and Definitions
Term | Definition |
Oral liquid formulation | A pediatric oral liquid formulation available on the drug market, provided by the pharmaceutical company |
Formulation manipulation | Change in (oral) drug formulation (e.g., crushing of tablets, opening of capsules, dissolving content in a vehicle) that is needed in clinical practice but is not described in the drug label |
BCS class | System to categorize drugs according to their permeability and solubility [95] BCS class I: high solubility, high permeability BCS class II: low solubility, high permeability BCS class III: high solubility, low permeability BCS class IV: low solubility, low permeability |
Solubility | The minimum solubility of the drug across a pH range from 1 to 8 and at a temperature of 37 ± 0.5 °C. High-solubility drugs are those with a ratio of dose to solubility volume that is less than or equal to 250 mL [95] |
Permeability | The effective human jejunal wall permeability of a drug. High-permeability drugs are generally those with an extent of absorption greater than or equal to 90% and are not associated with any documented instability in the gastrointestinal tract [95] |
Bioavailability | The extent and rate at which an active pharmaceutical ingredient (API) is absorbed in the systemic circulation and available at the site of drug action [95]. This is dependent upon the AUC, Cmax and Tmax of a medicinal product |
Bioequivalence | The term bioequivalence was introduced to ensure safety and efficacy and comparable in vivo performance of two medicinal products containing the same active substance. Bioequivalence between two medicinal products is assumed when the bioavailability (determined by a plasma concentration curve from which AUC, Cmax and Tmax can be calculated) is between 80% and 125% of the reference medicinal product. This is investigated in a bioequivalence or bioavailability study that meet the requirements of the study design described in the EMA or FDA bioequivalence guidelines and, as a main goal, investigates bioequivalence between two medicinal products containing the same active substance [9,10] |
Similar PK parameters | Similar PK parameters (i.e., AUC and Cmax) of the manipulated oral dosage form that are within 80–125% of the solid oral dosage form. This is typically shown in a PK study that as a main outcome calculated PK parameters and investigated treatment outcomes (such as toxicity and response) of an solid oral dosage form and as a secondary outcome included PK parameter calculations of manipulated oral dosage forms but do not meet the requirements of EMA or FDA bioequivalence guidelines [9,10] |
BCS = Biopharmaceutics Classification System; AUC = area under the curve; Cmax = maximum plasma concentration; EMA = European Medical Agency; FDA = U.S. Food and Drug Administration; PK = pharmacokinetics. |
Appendix A
Appendix A.1. General Search
Appendix A.2. Drug Formulation Search
Appendix B
Appendix C
TKI | Tradename | Dosage Form | Excipients 1 (Function) | |
---|---|---|---|---|
Tablet Core or Capsule Content | Tablet Film Coating or Capsule Shell | |||
BCS class I | ||||
Cobimetinib | Cotellic® (Roche) | Immediate release film-coated tablet 20 mg | Lactose monohydrate (diluent, compression) Microcrystalline cellulose (E460) (diluent) Croscarmellose sodium (E468) (binder, disintegrant) Magnesium stearate (E470b) (lubricant) | Polyvinyl alcohol Titanium dioxide (E171) Macrogol 3350 Talc (E553b) |
Ruxolitinib | Jakavi® (Novartis Pharma) | Immediate release film-coated tablet 5, 10, 15, 20 mg | Microcrystalline cellulose (diluent) Magnesium stearate (lubricant) Silica, colloidal anhydrous (glidant) Sodium starch glycolate (Type A) (disintegrant) Povidone K30 (binder) Hydroxypropylcellulose 300 to 600 cps (binder) Lactose monohydrate(diluent, direct compression excipient) | na |
Larotrectinib | Vitrakvi® (Bayer) | Immediate release hard capsule 25, 100 mg | na | Gelatin (shell) Titanium dioxide (E 171) (colourant) |
Oral solution 20 mg/mL | Purified water (solution base) Sucrose (suspending, sweetening agent) Hydroxypropylbetadex (?) Glycerol (E 422) (sweetening, antimicrobial preservative, solvent) Sorbitol (E 420) (sweetening agent) Sodium citrate (E 331) (emulsyfing agent) Sodium dihydrogen phosphate dihydrate (E 339) (buffer?) Citric acid (E 330) (buffer agent. antioxidant) Propylene glycol (E 1520) (solvent) Potassium sorbate (E 202) (solvent) Methyl parahydroxybenzoate (E 218) (antimicrobial preservative) Citrus fruit flavor (flavor) Natural flavor (flavor) | na | ||
BCS class II | ||||
Cabozantinib | CabometyxTM (Ipsen Farmaceutica) | Immediate release film-coated tablet 20, 40, 60 mg | Microcrystalline cellulose (diluent) Anhydrous lactose (diluent, compression excipient) Hydroxypropyl cellulose (disintegrant, binder) Croscarmellose sodium (disintegrant) Colloidal anhydrous silica (disintegrant) Magnesium stearate (lubricant) | Hypromellose 2910 Titanium dioxide (E171) Triacetin Iron oxide yellow (E172) |
Cometriq® (Ipsen Farmaceutica) | Immediate release hard capsule 20, 80 mg | Microcrystalline cellulose (diluent) Croscarmellose sodium (disintegrant) Sodium starch glycolate (disintegrant) Silica colloidal anhydrous (glidant) Stearic acid (lubricant) | Gelatin Black iron oxide (E172) (20 mg capsules only) Red iron oxide (E172) (80 mg capsules only) Titanium dioxide (E171) | |
Dabrafenib | Tafinlar® (Novartis Pharma) | Immediate release capsule 50, 75 mg | Microcrystalline cellulose (diluent) Magnesium stearate (lubricant) Colloidal silicone dioxide (glidant) | Hypromellose (E464) Red iron oxide (E172) Titanium dioxide (E171) |
Dasatinib | Sprycel® (Bristol-Meyers Squibb)2 | Immediate release film-coated tablet 20, 50, 70, 80, 100, 140 mg | Lactose monohydrate (diluent) Microcrystalline cellulose (diluent) Croscarmellose sodium (disintegrant) Hydroxypropylcellulose (disintegrant, binder) Magnesium stearate (lubricant) | Hypromellose Titanium dioxide (E171) Macrogol 400 |
Powder for suspension 10 mg/mL | Sucrose (suspending agent, sweetening, viscosity increasing agent) Carmellose sodium (viscosity increasing agent, adsorbent, emulsifying agent, suspending agent) Simethicone emulsion consisting of: simeticone, polyethylene glycol sorbitan tristearate, polyethoxylate stearate, glycerides, methylcellulose, xanthan gum, benzoic acid, sorbic acid, sulfuric acid. Tartaric acid Trisodium citrate anhydrous Sodium benzoate (E211) Silica hydrophobic colloidal Mixed berry flavour [containing benzyl alcohol, sulphur dioxide (E220)] | na | ||
Imatinib | Glivec® (Novartis Pharma)2 | Immediate release hard capsule 100 mg | Cellulose microcrystalline (diluent, compression agent) Crospovidone (lubricant, dispersing, solubilizing agent) Magnesium stearate (lubricant) Silica colloidal, anhydrous (disintegrant) | Gelatin Iron oxide, red (E172) Iron oxide, yellow (E172) Titanium dioxide (E171) |
Immediate release film-coated tablets 100, 400 mg | Cellulose microcrystalline (diluent) Crospovidone (disintegrating, solubilizing) Hypromellose (binder, solubilizing) Magnesium stearate (lubricant) Silica, colloidal anhydrous(disintegrant) | Iron oxide, red (E172) Iron oxide, yellow (E172) Macrogol Talc Hypromellose | ||
Ponatinib | Iclusig® (Incyte Biosciences) | Immediate release film-coated tablet 15, 30, 45 mg | Lactose monohydrate (diluent, compression excipient) Microcrystalline cellulose (diluent) Sodium starch glycolate (disintegrant) Colloidal anhydrous silica (disintegrant) Magnesium stearate (lubricant) | Talc Macrogol 4000 Poly(vinyl alcohol) Titanium dioxide (E171) |
BCS class IV | ||||
Bosutinib | Bosulif® (Pfizer) | Immediate release film-coated tablet 100, 400, 500 mg | Microcrystalline cellulose (E460) (diluent, compression agent) Croscarmellose sodium (E468) (disintegrant) Poloxamer 188 (binder, solubilizing agent) Povidone (E1201) (binder) Magnesium stearate (E470b) (lubricant) | Polyvinyl alcohol Titanium dioxide (E171) Macrogol 3350 Talc (E553b) Iron oxide yellow (E172) (100 and 400 mg only) Iron oxide red (E172) (400 and 500 mg tablet only) |
Crizotinib | Xalkori® (Pfizer) | Immediate release hard capsule 200, 250 mg | Colloidal anhydrous silica (disintegrant) Microcrystalline cellulose (diluent) Anhydrous calcium hydrogen phosphate (lubricant) Sodium starch glycolate (Type A) (disintegrant) Magnesium stearate (lubricant) | Gelatin Titanium dioxide (E171) Red iron oxide (E172) |
Entrectinib | Rozlytrek® (Roche) | Immediate release hard capsule 100, 200 mg | Tartaric acid (acidulant) Lactose (Diluent, compression agent) Hypromellose (binder, dispersing agent, solubilizing agent) Crospovidone (disintegrant, solubilizing agent) Microcrystalline cellulose (diluent) Colloidal anhydrous silica (disintegrant) Magnesium stearate (lubricant) | Hypromellose Titanium dioxide (E171) Yellow iron oxide (E172—100 mg hard capsule) Sunset yellow FCF (E110—200 mg hard capsule) |
Nilotinib | Tasigna® (Novartis Pharma) | Immediate release hard capsule 50, 150, 200 mg | Lactose monohydrate (diluent, compression agent) Crospovidone Type A (disintegrant, solubilizing agent) Poloxamer 188 (lubricant, solubilizing agent) Colloidal anhydrous silica (disintegrant) Magnesium stearate(lubricant) | Gelatin Titanium dioxide (E171) Red iron oxide (E172) (50 mg capsule only) Yellow iron oxide (E172) |
Selumetinib | Koselugo® (AstraZeneca) | Immediate release hard capsule 10, 25 mg | Vitamin E polyethylene glycol succinate (D α-tocopheryl polyethylene glycol succinate) (solubilizing agent, binder) | Hypromellose (E464) Carrageenan (E407) Potassium chloride (E508) Titanium dioxide (E171) Carnauba wax (E903)Indigo carmine aluminium lake (E132) (25 mg capsule only) Iron oxide yellow (E172) (25 mg capsule only) |
Sunitinib | Sutent® (Pfizer) 2 | Immediate release hard capsule 12.5, 25, 37.5, 50 mg | Mannitol (E421) (diluent) Croscarmellose sodium (binder, disintegrant) Povidone (K-25) (solubilizing agent, disintegrant) Magnesium stearate (lubricant) | Gelatin Red iron oxide (E172) Titanium dioxide (E171) Yellow iron oxide (E172) (25, 37.5, 50 mg capsule only) Black iron oxide (E172) (25, 50 mg capsule only) |
Trametinib | Mekinist® (Novartis Pharma) | Immediate release film-coated tablet 0.5, 2 mg | Mannitol (E421) (diluent) Microcrystalline cellulose (E460) (diluent) Hypromellose (E464) (binder, solubilizing agent) Croscarmellose sodium (E468) (binder, disintegrant) Magnesium stearate (E470b) (lubricant) Sodium laurilsulfate (lubricant, solubilizing agent) Colloidal silicon dioxide(E551) (disintegrant) | Hypromellose (E464) Titanium dioxide (E171) Polyethylene glycol Iron oxide yellow(E172) (0.5 mg tablet only) Polysorbate 80 (E433) (2 mg tablet only) Iron oxide red (E172) (2 mg tablet only) |
Appendix D
TKI | Study Design 1 | No. of Patients | Age Range (Years) | Tested Drug Formulations | Similar PK Parameters Demonstrated? | Refs |
---|---|---|---|---|---|---|
BCS class I | ||||||
Cobimetinib | - | - | - | - | - | - |
Larotrectinib | Phase 1 PK study | 24 | 0–18 | Capsules and oral liquid formulation 2 | Yes, between capsule and oral liquid 2 | [63] |
Ruxolitinib | Phase 1 PK study | 49 | 2–21 | Tablets and m.d.f 3 (i.e., crushed tablets or added to apple sauce or OraPlus) | No | [69] |
BCS class II | ||||||
Cabozantinib | Phase 1 PK study | 41 | 4–18 | Tablets | - | [70] |
Dabrafenib | Phase 1 PK study | 27 | 0–17 | Capsules and oral liquid formulation 2 (i.e., oral suspension) | No | [71] |
Dasatinib | Phase 1 PK study | 39 | 2–20 | Tablet, capsules and m.d.f 3 (i.e., crushed/dissolved in lemonade, apple or orange juice) | No | [72,73,74] |
Phase 1 PK study | 25 | 2–17 | ||||
Phase 1 PK study | 58 | 0–21 | ||||
Imatinib | Phase 1 PK study | 31 | 3–20 | Tablets, capsules and m.d.f 3 (i.e., opened or dissolved in water or apple juice) | No | [53,54,55,56,57,75] |
Phase I PK study | 24 | 3–21 | ||||
Phase II PK study | 24 | 2–18 | ||||
Phase II PK study | 71 | 3–29 | ||||
Phase II PK study | 19 | 2–18 | ||||
PK study | 36 | 2–22 | ||||
Ponatinib | - | - | - | - | - | - |
BCS class IV | ||||||
Bosutinib | - | - | - | - | - | - |
Crizotinib | Phase 1 PK study | 79 | 1–20 | Capsules and oral liquid formulation 2 (i.e., powder in a bottle, powder in capsule or oral liquid) | No | [58,59,60] |
Phase 1 PK study | 75 | 2–22 | ||||
Phase 1 PK study | 25 | 2–21 | ||||
Entrectinib | - | - | - | - | - | - |
Nilotinib | PK study | 15 | 5–17 | Capsules or sprinkled over apple sauce | No | [61] |
Selumetinib | Phase 1 PK study | 24 | 3–18 | Capsules, tablets | No | [62,64,65] |
Phase 1 PK study | 38 | 5–20 | ||||
Phase II PK study | 50 | 3–20 | ||||
Sunitinib | Phase 1 PK study | 23 | 3–20 | Capsule or m.d.f 3 (i.e., opened and sprinkled over yoghurt or applesauce) | Yes, between capsule and manipulated oral dosage form | [39,66,67,68] |
Phase 1 PK study | 12 | 4–21 | ||||
Phase II PK study | 30 | 3–20 | ||||
Phase I/II PK study | 6 | 13–16 | ||||
Trametinib | - | - | - | - | - | - |
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Crushed/Opened (Solid) Oral Administration (A) | LoE A | Oral Liquid (i.a. Nasogastric Tube Administration 1) (B) | LoE B | Refs | |
---|---|---|---|---|---|
BCS class I | |||||
Cobimetinib | Crush the tablet and administrate with a small amount of apple sauce or chocolate pasta | 5 | Dissolve the tablet in water and carefully stir/shake until the suspension is formed. Administrate the suspension immediately | 5 | [13,32,76] |
Larotrectinib | Use available oral solution | 1 | Use available oral solution | 1 | [37] |
Ruxolitinib | Crush the tablet and administrate with a small amount of apple sauce | 5 | Dissolve tablet in 40 mL of water and carefully stir/shake for 10 min. Administrate the suspension immediately | 1 | [24,38] |
BCS class II | |||||
Cabozantinib | Open capsule or crush the tablet and sprinkle content over a spoon of apple sauce | 5 | Dissolve tablet or content of capsule in apple juice and carefully stir/shake. Administrate the suspension immediately | 5 | [17,34,77] |
Cave: food interaction (higher AUC, Cmax and risk of toxicity) | |||||
Dabrafenib | Open the capsule and sprinkle content over a spoon of applesauce. Administrate the prepared suspension immediately | 5 | Dissolve capsule content in 5 mL water or apple juice and carefully stir/shake. Administrate the suspension immediately | 4 | [30,43,52,78] |
Cave: food interaction and chemical instable | |||||
Dasatinib | Use available oral suspension | 1 | Use available oral suspension | 1 | [35] |
Cave: antacid interaction, no bioequivalence between tablets and oral suspension | |||||
Imatinib | Open capsule or crush the tablet and sprinkle content over a spoon of applesauce | 5 | Dissolve 100 mg imatinib (capsule content or tablet) with 10 mL water. Administrate the suspension immediately | 1 | [31,45] |
Cave: do not mix imatinib with orange juice, milk or cola | |||||
Ponatinib | Crush the tablet and administrate with a small amount of applesauce | 5 | Dissolve tablet in lemon juice and carefully stir/shake. Administrate the suspension immediately | 5 | [15,19,46] |
Cave: only soluble in pH ≤ 2.0 | |||||
BCS class IV | |||||
Bosutinib | Crush tablet in a small amount of chocolate pasta | 4 | Dissolve tablet in apple juice and carefully stir/shake. Administrate the suspension immediately | 5 | [33,44,50] |
Cave: antacid interaction | |||||
Crizotinib | Open the capsule and sprinkle the content over a small amount of applce sauce | 5 | Dissolve capsule (with shell) in warm water (50 °C) and carefully stir/shake. Administrate the suspension immediately | 4 | [28,41] |
Entrectinib | Open the capsule and sprinkle the content over small amount of applesauce | 5 | Consider dissolving the capsule content in a low pH vehicle (e.g., lemon juice) | 5 | [29,47] |
Cave: not soluble and has non-standardized excipient (acidulant) in the formulation. Be aware of possible blocking of the feeding tube | |||||
Nilotinib | Open the capsule and sprinkle content over a spoon of apple sauce or chocolate pasta | 5 | Consider dissolving the capsule content in a low pH vehicle (e.g., lemon juice) due to insolubility of nilotinib | 5 | [23,25] |
Cave: food interaction and insolubility of nilotinib. Be aware of possible blocking of feeding tube | |||||
Selumetinib | Open the capsule and sprinkle the content over a small amount of applesauce | 5 | Consider dissolving the capsule content in a low pH vehicle (e.g., lemon juice) | 5 | [16,49] |
Cave: food interaction, low absorption in suspension formulation, use of non-standardized excipient (solubilizing agent) and insolubility of selumetinib. Be aware of possible blocking of feeding tube | |||||
Sunitinib | Open the capsule and sprinkle the content over applesauce (or yoghurt) | 2 | Dissolve capsule content in apple juice and carefully stir/shake. Administrate the suspension immediately | 2 | [26,39,40] |
Cave: sunitinib is light sensitive and will form (impure) isomers within two hours after dissolving in a glass of apple juice | |||||
Trametinib | Crush tablet and add content to a spoon of apple sauce | 5 | Dissolve tablet in 5 mL water or consider dissolving the tablet in a low pH vehicle (e.g., lemon or apple juice) and carefully stir. Administrate the suspension immediately | 4 | [21,27,42,43] |
Cave: food interaction and insolubility of trametinib. Be aware of possible blocking of feeding tube | |||||
General recommendations Always perform therapeutic drug monitoring (TDM) after manipulating the solid dosage form (see TDM recommendations in study of Janssen et al., 2020 [79]). Always use gloves and a mouth cap before manipulating the solid dosage form of anticancer drugs [80]. |
Off-Label Indication | Ligand | Log p | Solubility Range (pH) | pKa | Salt Form | Refs | |
---|---|---|---|---|---|---|---|
BCS Class I | |||||||
Cobimetinib | Solid tumors | MEK | 3.9 | 1.0–7.5 | - | Hemifumarate | [13,76] |
Larotrectinib | Solid tumors, Primary CNS tumors | TRK | 1.7 | 1.0–8.0 | - | Sulfate | [48,82] |
Ruxolitinib | Relapsed or refractory solid tumors, leukemia or myeloproliferative neoplasms | JAK | 2.1 | 1.0–8.0 | 0.91, 5.51, 13.89 | Phosphate | [20,83] |
BCS Class II | |||||||
Cabozantinib | HB, HCC | VEGF | 5.4 | 1.0–4.0 (capsules) 1.0–3.0 (tablets) | - | Malate | [17,18,77] |
Dabrafenib | LGG, HGG | B-RAF | 4.8 | 1.0–4.0 | −1.5 | Mesylate (and micronized, pharmaceutical development) | [52,78] |
Dasatinib | CML | BCR-ABL | 3.6 | - | - | Monohydrate | [36,84] |
Imatinib | CML, ALL | BCR-ABL | 3.5 | Soluble in water | - | Mesilate | [14,85] |
Ponatinib | CML, Ph+ ALL | BCR-ABL | 4.1 | 1.0–2.0 | 2.77, 7.8 | HCL | [15,86] |
BCS Class IV | |||||||
Bosutinib | CML | BCR-ABL | 5.4 | 1.0–5.0 | - | Monohydrate | [50,87,88] |
Crizotinib | ALCL | ALK | 1.65 | 1.6–8.2 | - | na | [22,89] |
Entrectinib | Solid tumors | ROS 1 and NTRK | 5.7 | Not soluble | - | na | [47,90] |
Nilotinib | Relapsed or refractory malignancies | BCR-ABL | 4.9 | - | 2.1, 5.4 | Monohydrate | [25,91] |
Selumetinib | Relapsed or refractory tumors | MEK | 3.6 | Not soluble | - | Hydrogen sulfate | [16,92] |
Sunitinib | Renal tumors | VEGF | 5.2 | 1.0–5.0 | 8.95 | Maleate | [51,93] |
Trametinib | LGG, HGG | MEK | 3.4 | Not soluble | - | Dimethyl sulfoxide | [21,94] |
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Bernsen, E.C.; Hogenes, V.J.; Nuijen, B.; Hanff, L.M.; Huitema, A.D.R.; Diekstra, M.H.M. Practical Recommendations for the Manipulation of Kinase Inhibitor Formulations to Age-Appropriate Dosage Forms. Pharmaceutics 2022, 14, 2834. https://doi.org/10.3390/pharmaceutics14122834
Bernsen EC, Hogenes VJ, Nuijen B, Hanff LM, Huitema ADR, Diekstra MHM. Practical Recommendations for the Manipulation of Kinase Inhibitor Formulations to Age-Appropriate Dosage Forms. Pharmaceutics. 2022; 14(12):2834. https://doi.org/10.3390/pharmaceutics14122834
Chicago/Turabian StyleBernsen, Emma C., Valery J. Hogenes, Bastiaan Nuijen, Lidwien M. Hanff, Alwin D. R. Huitema, and Meta H. M. Diekstra. 2022. "Practical Recommendations for the Manipulation of Kinase Inhibitor Formulations to Age-Appropriate Dosage Forms" Pharmaceutics 14, no. 12: 2834. https://doi.org/10.3390/pharmaceutics14122834
APA StyleBernsen, E. C., Hogenes, V. J., Nuijen, B., Hanff, L. M., Huitema, A. D. R., & Diekstra, M. H. M. (2022). Practical Recommendations for the Manipulation of Kinase Inhibitor Formulations to Age-Appropriate Dosage Forms. Pharmaceutics, 14(12), 2834. https://doi.org/10.3390/pharmaceutics14122834