2011LamPharmacotherapyFormulationsoralantineoplastic

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EXTEMPORANEOUS PREPARATION OF ORAL LIQUID ANTICANCER DRUGS Lam181differences in absolute bioavailability betweenthe oral solution and the solid dosage form mustbe minimized. When reviewing the literature,data on the bioavailability and pharmacokineticsof oral anticancer solid dosage forms administeredas a liquid suspension were scarce andfound only for a very few oral anticancer drugsincluding aminoglutethimide, 22 bexarotene, 28busulfan, 32 capecitabine, 3 etoposide, 51, 52 methotrexate,82–85 and sorafenib. 93 The bioavailabilityof these agents, except for busulfan, 32 whenextemporaneously prepared as an oral solution,was equal to that of solid dosage forms. Arandomized, crossover, bioavailability study witha washout period of 14 days was conducted in sixpatients receiving a single dose of aminoglutethimide500 mg as an oral solution. 22 Thetablets had a 9% larger mean area under theconcentration-time curve (AUC) value than thesolution and a 5% lower peak plasma concentration(C max ) value, which were not consideredto be significant differences. 22 The authorsconcluded that the bioavailability of oral tabletswas similar to that of oral solution. Anothergroup evaluated the pharmacokinetics of oralbusulfan in pediatric patients and reported wideinterpatient variability after oral administrationof the drug. 32 The investigators reported that thevariability may have been related to the differentadministration formulations of the drug (tablet,gelatin capsule, crushed tablet), administrationtechnique (nasogastric vs oral, administration ofcrushed vs intact tablets, administration ingelatin capsules), age, differences in bioavailability,and hepatic metabolism. It was suggestedthat drug monitoring and patient-specific dosageadjustment should be considered.Capecitabine tablets are supplied as immediatereleaseand film-coated tablets, and are watersoluble. 3 One pharmacokinetic study evaluatedpatients with solid tumors who were given asolution of a single dose of capecitabine 2000mg; the drug was provided in powder form andreconstituted in 200 ml of water. 3 The studyshowed that the absorption of the drug was rapidand almost complete. Eighty-four percent of thedose was recovered in the urine in the first 12hours, indicating rapid excretion of capecitabineand its metabolites.Two pharmacokinetic studies evaluated thebioavailability of oral etoposide solution prepared51, 52from the intravenous etoposide solution. Aphase I study evaluated the pharmacokineticsand pharmacodynamics of oral etoposide 25–75mg/m 2 /day as three equally divided daily dosesfor 21 days in pediatric patients with solidtumors. 51 Etoposide oral solution was preparedas a 1:2 dilution of intravenous etoposidesolution with 0.9% normal saline solution.Patients were instructed to further dilute eachdose immediately before administration either inorange juice, lemonade, apple juice, or flavoredsyrup. Pharmacokinetic data were collected onday 1 of therapy in 18 children and again on day21 in 14 of those patients. The bioavailability oforal etoposide solution in the study was assumedto be 50% of the intravenous doses. The resultsindicated no significant difference between theAUC values measured on days 1 and 21, althoughthe pharmacokinetic results revealed substantialintrapatient variability. The degree of neutropeniacorrelated best with the duration of systemicexposure to the drug when the steady-stateplasma concentration was maintained above 1µg/ml, rather than the AUC, C max , dose, or otherpatient characteristics.In the second study, the bioavailability ofetoposide was examined after oral administrationof a single dose of intravenous etoposide solutionin eight adult patients with cancer. 52 A dose oforal etoposide 50 mg (2.5 ml) was prepared from20-mg/ml intravenous etoposide solution, andwas further diluted in 100 ml of water. Thepatients were instructed to take the dose after anovernight fast, 30 minutes before breakfast.Multiple blood samples were collected at differenttime intervals after oral administration fordetermining the plasma etoposide concentrationby using HPLC, as well as pharmacokineticparameters such as C max , time to reach C max , andAUC. Plasma concentrations of etoposide wereabove 1 µg/ml in seven of eight patients, and themean C max , time to C max , half-life, and AUC were2.38 µg/ml, 1.19 hours, 7.5 hours, and 12.83µg•hour/ml, respectively. The authors used thepharmacokinetic data of other studies in whichthe therapeutic responses could be achieved witha mean plasma etoposide concentration of 1µg/ml to conclude that intravenous etoposidesolution produced adequate bioavailability51, 53compared with the oral capsule form. Thelimitation of both studies was that there was nota direct comparison with the control in a crossoverdesign.One pharmacokinetic study of methotrexateevaluated the effect of subdivision of the doseusing three different formulations (oral tablets,oral liquid, and intravenous infusion) and thetiming of the methotrexate within the chemotherapycycle. 82 The patients in the study acted
182PHARMACOTHERAPY Volume 31, Number 2, 2011as their own controls. A 2-mg/ml oral solutionwas prepared from mixing methotrexate injectionwith sodium bicarbonate, syrup, and chloroformwater. The results showed that mean bioavailabilityfor all the oral methods of administrationwas 28% of the same dose given intravenously.There were no significant differences in terms ofabsorption, AUC, and C max between oral tabletsand the extemporaneous oral liquid. 81 Theseresults were consistent with those of otherpharmacokinetic studies. 83–85The bioavailability of sorafenib tablets administeredas a liquid suspension compared withintact tablets was evaluated in a crossovermanner. 93 Twenty-six healthy male volunteerswere randomized into two groups who receivedeither two 200-mg tablets administered with 8 ozof water or an oral suspension of two 200-mgtablets disintegrated in 2 oz of water over 10minutes, followed by oz of water for rinsing.The two study arms were separated by a 10–14-day washout period. Serial blood samples werecollected before, immediately after, and for up to144 hours after each dose of sorafenib. Sorafenibwas assayed by liquid chromatography–massspectrometry, and AUC, C max , and time to C maxwere assessed. There was no significant differencein absorption and in the geometric means ofthe pharmacokinetic parameters between the twogroups. The mean relative bioavailability ofsorafenib tablets was 38–49% compared with oralsolution. Although the clinical significance ofthis bioavailability finding is unknown, caution isadvised if sorafenib is administered as an oralsolution. Patients should be monitored forpotential increased toxicities of the drug. Nopharmacokinetic data of the oral sorafenibsolution using any fluids other than water wereavailable. Neither the stability of oral sorafenibsuspension nor the administration of thesuspension through a feeding tube was studied.Therefore, it is advised that the suspension beadministered within 1 hour after preparation. 93PalatabilityYoung children and the elderly often havedifficulty swallowing solid dosage forms. Smallpill size or liquid dosage forms are better suitedfor these patient populations. The main problemwith using an oral liquid is its palatability sincetaste sensation differs from one person to anotherand is age dependent. 143 The appropriate choiceof taste, odor, color, palatability, and sweetness ofan oral liquid preparation may encourage drugtherapy adherence, especially in children. 142 Theactive ingredient of some of the drugs mayproduce an unpleasant taste, and the manufacturerusually applies a flavored sweetened filmcoating onto the tablets to improve palatability. 143Most oral anticancer drugs are also surroundedby a wax matrix to prevent exposure to thehealth care worker. If these tablets are crushed,the patient would be subjected to the unpleasanttaste, which could impair drug adherence.Alternative Delivery Methods toExtemporaneous Oral Liquid FormulationsWhen a patient cannot swallow a tablet orcapsule, a commercially available oral liquidformulation should be preferred before consideringthe extemporaneous compounding method.Examples of oral anticancer liquid formulationsthat are commercially available include megestrol18, 19and tamoxifen.Ideally, the source of an active drug for preparationof an extemporaneous oral liquid shouldbe a pure drug. Since the pure drug is usuallynot easily available, it is common practice toobtain the pure drug from injectables, tablets, orcapsules.Crushing Tablets or Opening CapsulesThe most common method of preparing anextemporaneous oral liquid formulation from thesolid dosage form is pulverization using a mortarand pestle. 140 Before a tablet is crushed or acapsule is opened to empty the contents, it isimportant to understand the pharmacokinetics ofthe drug and to research if any stability data areavailable in the literature. Almost all oralanticancer agent tablets are film coated to protectthe handler from direct contact with the activeingredient. In addition, a coating is necessary fortablets that have an unpleasant taste, and asmoother finish makes large tablets easier toswallow. 143 Coatings are also useful to extend theshelf-life of pharmaceutical ingredients that aresensitive to moisture or oxidation. 143The practice of crushing a tablet or opening acapsule of an oral anticancer agent is generallynot recommended because it raises the concernof unreliable dosing as well as posing a hazard tohuman health. Certain tablets, although they arenot designed to be extended release or entericcoated, may not be crushed because it can alterthe pharmacokinetics or bioavailability of thedrug. For example, a pharmacokinetic study
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2011LamPharmacotherapyFormulationsoralantineoplastic

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