It is widely known that the majority of new chemical entities (NCEs) failed to achieve commercial status given unacceptable toxicity or insufficient efficacy that may be associated to suboptimal pharmacokinetic proper-ties. Toxicity, efficacy and pharmacokinetic properties in humans are difficult to predict despite sophisticated in-silico approaches, allometric scaling,[1–3] and new genomic-based approaches.[4]
The question that this paper attempts to address is: if unacceptable toxicity or sub-optimal pharmacoki-netic properties are predicted or are observed during clinical trials, could these risks be mitigated by utilizing innovative formulation approaches? This paper pres-ents various conventional and novel oral dosage for-mulation approaches, including examples of marketed
technologies and interesting research that are intended to mitigate or control undesirable side effects and at the same time improve or maintain the desired blood plasma drug concentration (C
max), half life (T
1/2) and other phar-
macokinetic parameters. The paper is concluded by an overview of regulatory opportunities and constraints to be considered when reformulating or optimizing a mar-keted drug.
To initiate a first-in-man clinical trial, short-term toxicology studies are required in one rodent (normally rats) and in one nonrodent species (preferably dogs, if not monkeys).[5] Due to inherent differences in inter-species absorption, distribution, metabolism and elimination (ADME), different species are known to exhibit varying exposure and toxicity to the same formulation. In many cases, a formulation that provides great oral exposure in
REVIEW ARTICLE
Formulation approaches in mitigating toxicity of orally administrated drugs
Irina Kadiyala1 and Elijah Tan2
1Formulation Department, Vertex Pharmaceuticals, Cambridge, MA, USA and 2Department of Regulatory Affairs, Biogen Idec, Cambridge, MA, USA
AbstractThis paper provides an overview of current formulation approaches to mitigate toxicity of orally administrated drugs. The formulation approaches are characterized by their intended impact on a drug’s pharmacokinetic parameters, pharmacological properties or metabolic pathways. Regulatory opportunities and constraints with focus on U.S. regulations in optimizing a drug’s safety or efficacy profile are reviewed. The following formulation approaches are described: (i) pharmacokinetic-modulating and (ii) pharmacodynamic-modulating. In the pharmacokinetic-modulating approach, the pharmacokinetic profile of drug release is modified by, for example, a reduction in peak drug plasma concentration while preserving or improving AUC, thereby potentially reducing toxic effects that may be related to Cmax. In the pharmacodynamic-modulating approach, the drug is co-dosed with pharmacologically active or nonpharmacologically active agent or agents intended for mitigation of the drug’s toxicity. The pharmacodynamic-modulating approach requires information on the specificity of drug interactions with other compounds and also on metabolic pathways. Examples demonstrating successful formulation work in reducing drug toxicity are provided. The in-depth knowledge of the drug’s PK and PD properties combined with a greater understanding of the biology of diseases are necessary for successful drug product formulation leading to optimized in vivo exposure and minimized toxicity.Keywords: Formulation, oral, toxicity
Address for Correspondence: Irina Kadiyala, Formulation Department, Vertex Pharmaceuticals, 130 Waverly Street, Cambridge, MA 02139-04242, USA. E-mail: [email protected]
(Received 04 June 2012; revised 19 August 2012; accepted 19 September 2012)
rats has only limited exposure in a nonrodent species. Often, early-phase formulations are not optimized for stability, administration convenience or marketability, and need to be dosed shortly after preparation to obtain essential information on pharmacokinetic (PK) and toxicology profiles. There is a certain expectation that the resulting formulation used to support early toxicology studies is not only relatively stable, but is also optimized for in vivo exposure since adequate exposure is required for prediction of exposure and differences in PK profiles between species.
To reach the needed clinical exposure or exposure needed for a nonclinical toxicology study, formula-tors may explore nonconventional technologies, such as spray-drying or melt granulation, in addition to the standard arsenal of common particle size-reduction techniques for poorly water soluble drugs. Innovative formulation approaches are often credited for render-ing a particularly insoluble drug soluble or for improv-ing the pharmacokinetic properties of a drug in an effort to boost efficacy or to reduce dosing frequency. However, formulation modification and optimization are often overlooked as potentially viable options for reducing or modulating the observed or predicted tox-icity of a drug.
Options for modulating toxicity in orally administered formulationsDrug delivery systems or formulations for oral dosage forms might potentially reduce toxicity by
1. lowering the plasma drug concentration peak below the toxicity level but maintaining the drug concen-tration above the clinical efficacious or therapeutic level;
2. imparting targeted delivery of the drug to the intended absorption site within the gastrointestinal system such as the stomach, intestine, or colon; or
3. co-administrating with other pharmacologically active agent or agents to modulate the expected tox-icity of a drug.
How long and how much a drug remains in the body or drug exposure is measured by the area under the plasma drug concentration-vs-time curve (AUC). Two drug product formulations containing the same active pharmaceutical ingredient and having similar AUC value may give different efficacy and/or safety profile if the time course of absorption is different. The for-mulation having a fast C
max may elicit an adverse reac-
tion, whereas the one having a flatter and prolonged profile with a lower ratio of peak maximum to trough concentration may not. The formulation providing a flatter and prolonged concentration exposure may be able to maintain the plasma drug concentration above the therapeutic level without exceeding the toxic level while preserving the same AUC. Therefore, simply reducing the administered dose may not be appropriate or ideal. Depending on the pharmacology, the critical
PK parameter may be AUC/critical concentration, time/critical concentration, C
trough, or C
max/critical concentra-
tion. Formulations can be optimized for any of these parameters. However, to achieve an understanding of which parameters are critical takes significant time and effort, especially for a drug with a novel mechanism of action.
In general, the formulation approaches to mitigating toxicity of oral formulations can be divided into two gen-eral categories:
1. pharmacokinetic-modulating approaches, which include targeted delivery systems and
2. pharmacodynamic-modulating approaches that uti-lize co-administration of other compounds to modify the pharmacological profile of the active compound.
The chosen names reflect the nature of these formu-lation approaches. The following sections will provide details on the approaches. It should be stressed that the objective of this paper is not to cover in depth all of the available formulation techniques and technologies. The goals of this review are to illuminate the complexity of the undertaking and to describe the arsenal of tools avail-able in an attempt to mitigate the toxicity of a drug. In conjunction with regulatory considerations, the authors hope that this paper can be useful in guiding the selec-tion of the optimal formulation path to mitigate expected toxicities of orally administered drugs.
Pharmacokinetic-modulating formulation approachesThe pharmacokinetic profile of a drug can be modified by a change in its physical properties (e.g. change in par-ticle size of the API), a change in its immediate physical environment (e.g. change in polarity or pH of its environ-ment), or a change in the rate at which a drug is released from a formulation matrix (e.g. use of controlled release formulation (CR)). Lipid-based systems and targeted delivery systems belong to a subset of the pharmacoki-netic-modulating system since in all known cases they modify PK parameters.
An overview of several pharmacokinetic-modulating delivery options for formulation approaches that can potentially mitigate toxicity by modulating human PK is listed in Table 1. All of these systems serve to lower C
max below the toxic level while maintaining the concen-
tration above the therapeutic level. Some formulation approaches are difficult to precisely categorize, e.g. a controlled-release formulation that is lipid based and utilizes site-specific delivery, since these approaches can be assigned to more than one category. Details and examples of these systems are presented in the following sections.
Controlled release (CR) formulationA CR formulation modifies the pharmacokinetic profile of a drug by reducing its peak concentration (C
max) while
prolonging its absorption phase. Thus, it can potentially mitigate the toxic effect of the drug and enhance patient
compliance by reducing dosing frequency. However, the CR formulation may result in overdosing by sys-temic accumulation of the drug when coupled with a low clearance factor. To overcome this possibility, an accurate prediction of the drug dose is essential, and the prediction has to be based on physicochemical, PK and pharmacological properties of the drug. Drugs with slower absorption rate and optimal half-life provide less fluctuation in plasma concentration, maintain the desired therapeutic concentration over a longer period, and thereby allow less frequent dosing. Drugs with a short half-life, large distribution volume, and narrow therapeutic window or low therapeutic index would usually obligate frequent dosing, and are often consid-ered good candidates for controlled release formula-tion (e.g. carbamazepine, nifedipine, clarithromycin). However, there are known examples of drugs with a
long half-life formulated as a CR formulation (e.g. phe-nobarbital, diazepam).
The following are only a few examples of CR formu-lations contributing to lower incidence of observed adverse events.
• Zonegran (Eisai) is an antiseizure drug with a long half-life: up to 2 weeks may be required to achieve steady state. Orexigen Therapeutics developed a new controlled release formulation, containing the same active ingredient, with improved tolerability when compared to the immediate release formula-tion. In the Phase I clinical study, the new controlled released formulation of zonisamide (zonegran) achieved a significant reduction in the incidence of spontaneous adverse events compared to the imme-diate release formulation.[8]
Table 1. Examples of pharmacokinetic-modulating formulation approaches in humans. Formulation Toxicity mitigation Consideration(s)Controlled release formulation
Reduce Cmax
while maintaining similar AUC or raise AUC to mitigate toxic effects while prolonging desired pharmacological effect. The lower C
max can contribute to toxicity
mitigation.
Food effect might have an effect on PK profile.Improve patient compliance due to less frequent dosing regiment.Breakdown in physical integrity of the dosage form may lead to overdose or departure from intended PK profile.[6]
In using CR products to minimize bioavailability variation, factors such as metabolizing enzymes, permeability variations and available GI area for absorption should be considered.Difficulty in tailoring dosing regimen to coincide with patient’s circadian rhythm.Enhanced bioavailability and minimize variability, e.g. with gastro-retentive preparations
Site-specific delivery or targeted delivery, e.g. to colon by enzyme specificity (can be viewed as subset of the controlled release formulation)
Increase bioavailability and circumvent absorption in areas of the GI track associated with adverse reactions.
Maximize effectiveness of the dose delivery.Intra-species variability in exposure.Possible sensitivity to timing of food intake as a result of varying GI motility with and without food.Limited absorption window.For colonic delivery, an absence of preclinical models to screen and evaluate efficacy of formulations; humans remain to be the best model for optimization of formulations for colonic delivery
Mucoadhesive Increase bioavailability and circumvent absorption in areas of the GI track associated with adverse reaction
Continuous excretion of mucous by the gastric mucosa and stomach contractions impact binding of the mucoadhesive systems to the stom-ach wall.Patients with certain types of diseases that modify absorption or certain patient population (e.g. geriatric patients or patients with inflamma-tory bowel disease) may not be suitable mucoadhesive-based delivery systems.
Lipid-based systems Increase bioavailability through increased solubility of nonpolar drugs while requiring less drug hence lowering C
max to achieve intended
pharmacological effect. The lower C
max can contribute to toxicity
mitigation.
Enable delivery through lymphatic circulation for drugs with solubility of >50 mg/mL in long chain fatty acids.[7]
Similar to taking drugs with fatty food. However, to overcome the food effect, a high amount of lipid is required, which might not be practical.Normally, it is difficult to optimize formulations in vitro due to chal-lenges with simulating in vivo conditions (e.g. lipase activity) with in vitro assays (e.g. dissolution).Variability in bioavailability is often a result of patient specificity.
Active transport Increase bioavailability while requir-ing less drug hence lower C
max to
achieve intended pharmacological effect. The lower C
max can contribute
to toxicity mitigation.
Mechanism of active transport is not always understood.Intra-species variability in exposure.
Modification of drug by covalent or noncovalent attachment to polymeric matrix or prodrug.
Increase bioavailability while lower-ing C
max through chemical stabili-
zation of the molecule or through site-specific delivery. The lower C
max
can contribute to toxicity mitigation.
Chemical instability of the linkage.Variability in drug performance due to dependence of drug release on in vivo environment.
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• The CR formulated nifedipine (Ca-channel blocker is used for high blood pressure treatment and slow down labor) prolongs the therapeutic effect of the drug while reducing undesired effects such as flush-ing, dizziness, and hypotension when compared to the conventional IR formulation.[9,10] The hypo-tension is attributed to the initial spike of the drug concentration in blood when the immediate release nifedipine is administered. This hypotensive effect can sometimes result in death.[11]
• The CR formulated theophylline (respiratory condi-tions, e.g. whizzing, asthma) circumvents transient nausea and GI irritation induced by even sub-toxic concentrations of the drug in the immediate release products.[12] Toxicity mitigation with the CR formu-lated might be explained by lower C
max for the CR
formulation vs IR formulation.[13]
• Multiple examples of CR formulations for antidepres-sants (e.g. paroxitine XR) were reported.[14] Intolerable nausea with an IR formulation despite seeing improve-ment in patient’s depressive symptoms subsided in many cases when patients switched to CR formula-tions. Overall, tolerability to the drugs was improved leading to better patient and physician compliance.
• In open-label studies, switching from conventional IR to CR formulations of carbamazepine reportedly improved compliance and seizure control or toler-ability, particularly for tremor.[15]
For development of a CR formulation, knowledge of physicochemical and pharmacological properties, target delivery site, and resulting metabolites, as well as evalu-ation of a food effect on PK are crucial. For illustration, the drug ebastine forms an active metabolite that has a long clearance time.[16] In this particular case, conversion of ebastine to its active metabolite does not affect any changes to its toxicology profile. However, this example illustrates the point that knowledge of the properties of active metabolites is crucial in establishing safety mar-gins for any drug.
Unfortunately, even the use of a wisely designed CR formulation does not guarantee the complete elimina-tion of toxic side effects, and the toxicity target could also change. For example, patients taking an immediate-release nifedipine product may suffer from hypotension while those taking the CR formulation may experience hypotension as well as reflex tachycardia.[17] In some of the cases, formulation work cannot overcome toxicity of the drug due to its systemic toxicity. However, use of site specific or targeted delivery approaches may prove to be beneficial in terms of improving the safety profile as demonstrated below.
Site-specific or targeted deliveryFormulations that enable targeted delivery to a specific part of the GI tract are considered a subset of controlled delivery systems. To avoid systemic toxicity caused by drugs in the treatment of ulcerative colitis in the proximal
segments of the small intestine, the microencapsulated beads delivering 5-aminosalicyclic acid or budenoside were designed to deliver the drug close to the site of inflammation.[9] Another example is Myfortic, myco-phenolic acid, an immunosuppressant drug by Novartis for use during organ transplantation. In addition to the common side effects of immunosuppressants, this drug also caused nausea and irritation to the stomach lining. Recently, Myfortic has been developed as a new enteric-coated formulation in order to protect the upper gastro-intestinal tract from damage thereby lessening stomach irritation.
Another type of site specific delivery is gastroretentive formulations designed to increase exposure of the drugs with a narrow absorption window in the upper duode-num. An example of this technology is Depomed’s for-mulation platform that keeps a drug depot in stomach; and feeding a soluble portion of the drug to the small intestine at a certain rate. Depomed successfully refor-mulated Gabapendin from an immediate release formu-lation to a CR formulation. The CR formulation increased the stomach residence time to 6–8 h from a regular 2 h in a fasted state thus improving patient compliance, achiev-ing higher bioavailability at higher doses and mitigating potential side effects.[18]
Mucoadhesive deliveryMucoadhesive delivery system could also be considered a subset of the controlled delivery systems. Regardless of the continued interest in this system for the past years, there is a lot of skepticism about its successes concern-ing its true mechanism of action (see the Table 1). There are plenty of examples of various polymers used for mucoadhesive delivery in the stomach or in the colon.[19] However, specific examples of whether the mucoadhe-sive delivery system that can contribute to reduced toxic-ity are not available.
NCE-modification: prodrugA prodrug is a pharmacological substance that is admin-istered in a pharmacologically inactive (or significantly less active) form. Once administered, the prodrug is metabolized in vivo into an active metabolite. The pro-drug approach is normally employed to address in vivo permeability or stability issues of the drug. There are several marketed prodrug formulations utilizing this approach such as enalapril (Merck) and lisdexamfet-amine (Vyvanse®, Shire Pharmaceuticals). However, the prodrug can also be used to reduce drug toxicity. Currently, prodrugs are widely used to deliver cytotoxic drugs. For example, the peroral delivery of the prodrug 5-iodo-2′-deoxyuridine showed less systemic exposure than its parent compound delivered by IV route.[20]
Lipid-based formulationsThe lipid delivery system operates as a controlled deliv-ery system modifying the pharmacokinetic parameters by extending GI transit time, changing dissolution rate
due to lipid digestion products, lipoprotein binding and distribution within systemic circulation (CL and Vd changes),[21] and a probable impact on enterocyte-based metabolism and/or efflux pumps.[22] Depending on the formulation composition such as the presence of long chain fatty acids, the delivery could be done through lymphatic system, which could improve in vivo per-formance, but not necessarily modulate the toxicology profile.[23]
Lipid-based formulations designed for controlled-release delivery are shown to mitigate toxicity of encap-sulated drugs versus the neat drug due to control of peak plasma concentration, alteration of disposition kinetics, and possibly a change in the target delivery site. A clas-sic example of using lipids to reduce toxicity is formula-tion of Amphotericin B. Amphotericin B is the principal choice against fungal infections,[24] and its application is limited by its high kidney toxicity and preferred IV route of administration requiring slow IV injections. There is plenty of evidence in the literature showing dependence of toxicity reduction for Amphotericin B on formula-tion composition and particle size.[25] The company BioDelivery Sciences International (BDSI) claimed that by encapsulating amphotericin B in cochleate (Bioral Amphotericin B, BDSI), a significant reduction in com-pound’s toxicity and an increase in efficacy was achieved.
Another interesting example is co-administration of Paclitaxel with cyclosporine. Paclitaxel is widely used in treating advanced ovarian and breast cancer. When delivered by IV infusion, severe hypersensitivity is observed due to a solubilizing vehicle used, Cremophor EL. The oral route is always attractive because of its convenience for patients and may circumvent sys-temic exposure to the vehicle Cremophor EL. However, paclitaxel has very poor oral bioavailability because of its affinity for the membrane-bound drug efflux pump P-glycoprotein. As shown in preclinical and clinical studies, Paclitaxal oral exposure was approximately eight-fold increase in the systemic exposure of oral paclitaxel when co-dosed with cyclosporine, which is an efficacious inhibitor of P-gp, and CYP 3A4–mediated drug metabolism, and at the same time toxicity observed after oral administration was graded as mild, whereas by IV, severe adverse effects were observed.[26,27] Some of the lipid delivery systems, which have a solubility and/or permeability enhancer in their composition, may form complexes leading to improved solubility and thus preventing drug precipitation in the GI and reducing local irritation upon contact with the GI wall.
Active transportThis formulation delivery approach involves receptor-mediated transport delivery. There is a substantial number of transporters varying in structure to support transport of different molecules to different cells. In gen-eral, active transport may help lessen toxicity under the same premise of the targeted delivery system discussed above.
Pharmacodynamic-modulating approach
A pharmacodynamic-modulating approach (or co-administrating approach), depending on the chemical properties or biological activity of the co-administered compound, renders a response from engaged bio-logical targets. For the pharmacodynamic-modulating approach, the added agent may be intended to control or mitigate toxicity manifestations although the phar-macokinetic profile (e.g. AUC or C
max) may or may not be
impacted by the addition.Pharmacodynamic-modulating formulation systems
are created based on the knowledge of biochemical behavior and metabolic pathways of a drug and its spe-cific interaction with the co-administered compound(s). Knowledge of drug metabolites and site of biological action is also of great importance. Modulating toxicity can be attempted by blocking or stimulating certain met-abolic pathways, or by scavenging the toxic metabolites of the drug.
Some specific examples illustrating reduced toxicity of a drug product containing a pharmacodynamic-modu-lating agent versus the naïve drug are listed below.
• Reduction of toxicity of antineoplastic drugs by co-administration with protective agents that are sulfhy-dryl moieties and/or reducible disulfides.[28]
• Nitric oxide donors are claimed to reduce toxicity caused by drugs to GI by inhibiting the HCl-induced mucosal lesions mainly through prostaglandin.[29] For example, nitric oxide-releasing aspirin has lower GI toxicity than conventional aspirin.[30]
• In order to avoid drug-drug toxicity in patients under-going concurrent administration with other drugs, such as antidepressants, d-threo-methylphenidate is formulated with drugs whose metabolism is known to occur via the cytochrome P450 enzyme.[31]
• Antibodies are used with anti-inflammatory drugs to block the release of harmful cytokines, e.g. SB-210396 and SB-217966 by SmithKline Beecham.[32]
It can be inferred from the above examples that because every drug has its unique pharmacological property, the approach for reducing or controlling a drug’s toxicity by co-administration with another compound will likely dif-fer from one drug to another.
Food intake dependencesIn addition to formulation considerations, the effect of food on bioavailability and toxicity should also be con-sidered. Food taken together with an orally administered drug can sometimes mitigate the drug’s adverse effect and/or increase its bioavailability. Factors for bioavail-ability enhancement include:
• Increased absorption through an increase in gastric-retention transit time[33]
• Increased solubility in the presence of bile acids induced by food with high lipid content, or increased dissolution of basic drugs with increased
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secretion of acidic gastric enzymes triggered by food consumption[34]
• Increased absorption through direct coupling with food molecules.[35]
Food intake does not always promote drug absorp-tion and normally is a cause of higher absorption vari-ability. Levothyroxine (Levoxyl, Synthroid) is the drug for hypothyroidism. Levothyroxine’s absorption is adversely affected by certain foods.[36] The effect of food on a drug is dependent on variables such as formulation, drug’s therapeutic index, type and size of meal, dose-response curve, and time difference between meal and medication intake.[34]
The effect of food on drug toxicity is less direct than on absorption. Drugs taken directly with food can sometimes limit GI irritation. When food has a posi-tive effect on absorption, a reduction of total drug dose may result in reduction of the drug’s irritating effect or overall toxicity. In the case of CR theophylline prod-ucts, increased absorption in the presence of food can potentially increase toxicity in patients who have been stabilized on drug levels obtained under fasting condi-tions.[34] However, in designing formulations it is not desirable to rely solely on control of food intake to regu-late drug absorption or toxicity given the lack of control over a patient’s dosing behavior and the nature of meals a patient will have. Other options, such as the application of a controlled-delivery system or co-administration with protective agents, should be explored.
Another, a well-known example of the food effect, either positive or negative, is an effect of the grapefruit juice on the altering PK through inhibition of metaboliz-ing enzymes and/or transporters in the GI tract.[37] It is apparent that this effect might have serious implications drugs intended to treat life-threatening conditions such as cancers or life-threatening infections. Naringin, flavo-noid component in fruits and vegetables, was found to be a major factor responsible for the drug-food interactions, and other juices tested such as apple and orange clini-cally demonstrated this effect.[38]
Regulatory considerations
Taking an already FDA-approved or marketed drug and modifying its pharmacokinetics profile or pharmaco-dynamics behavior can have regulatory consequences, even if the modification is intended to improve the safety or efficacy of the drug. Section 201(p)(1) of the United States Federal Food, Drug and Cosmetic Act (FD & C Act) defines a New Drug as any drug with a composition that is not generally recognized as safe and effective for use for which it is labeled. A New Drug does not have to be a new chemical entity or a new molecular entity. Under United States Code of Federal Regulations (21 CFR Part 310.3) a drug is considered a New Drug if:
• there is a new drug use of any substance that com-poses the drug,
• there is a new drug use of a combination of approved drugs,
• the proportion of ingredients in combination is changed (i.e. a major change is made to the existing formulation composition),
• there is a new intended use for the drug or• the dosage, method or duration of administration or
application is changed.
Marketing or commercialization of a New Drug in the United States requires approval by the Food and Drug Administration via a New Drug Application (NDA) or a Biologics License Application (BLA). A New Drug is subject to a myriad of regulations governing all stages of its development. Therefore, it is important to con-sider whether a change in the route of administration or a change in the formulation, even for the purposes of enhancing safety or efficacy, may render an already approved drug a New Drug. The 2004 FDA Guidance for Industry “Submitting Separate Marketing Applications and Clinical Data for Purposes of Assessing User Fees” recommends that a change in the composition of an approved product to support a change in the dosage form or route of administration should be submitted as a separate original application (NDA or BLA). However, if a formulation change (including a change in strength or concentration) does not also involve a change in dos-age form or route of administration, such a change can typically be submitted as a supplement to the approved application (e.g. sNDA or sBLA). Determining whether a change can be made under a supplemental application versus an original application is important because sup-plemental applications have significantly higher level of review priority under the Prescription Drug User Fee Act (PDUFA), hence the sponsor may obtain faster approval of the changed drug product.
A less well-known regulatory pathway, described in Section 505(b)(2) of the FD&C Act, may potentially yield significant cost- and time-saving for a sponsor who intends to introduce changes to a previously approved product but has not obtained a right of reference from the marketing authorization holder of the approved product. According to the FDA’s 1999 Draft Guidance on 505(b)(2) applications, an applicant should submit a 505(b)(2) application for a change in a drug when approval of the application relies on the FDA’s previous finding of safety and/or effectiveness for a drug. The changes to approved drugs which would fall under the 505(b)(2) include changes in dosage form, strength, route of administra-tion, substitution of an active ingredient in a combination product, formulation, dosing regimen, or even indica-tion. The cost- and time-saving potential of a 505(b)(2) application is derived from the applicant’s ability to reference published scientific literature and/or approved NDA/BLA as primary bases of approval, thus limiting the extent of necessary nonclinical and clinical trials that the 505(b)(2) applicant needs to conduct to demon-strate safety and efficacy of the New Drug. Additionally,
a 505(b)(2) application may qualify for additional years of market exclusivity depending on the scope of clinical studies conducted or sponsored by the applicant.
Since a change to an approved drug to optimize bio-availability or safety will most likely require approval of an original NDA or BLA, an sNDA or sBLA or potentially a 505(b)(2) application supported by additional clinical and/or nonclinical studies, the sponsor of a New Drug should consider, during preclinical or early clinical devel-opment, whether to heavily invest into the optimization of a formulation for bioavailability or safety, or to opt for the first feasible formulation and postpone product optimiza-tion until the original drug is in advanced stages of clini-cal development or after the original drug is approved for marketing. This consideration often includes nonregula-tory factors such as patent period, marketing competition, and other economic factors. Specifically, a fast-to-market strategy may be preferred over an ideal formulation if the sponsor can achieve the first-therapeutic-in-line status for the drug. In the case of diseases with an unmet medi-cal need, being the first product to market can often lead to a tremendous competitive advantage for the sponsor.
It is also important to consider whether an excipient intended for use in the formulation of a drug has been used in an approved drug product and used for a particu-lar route of administration. The FDA considers excipients that physically or chemically combine with active ingre-dients to facilitate drug transport as inactive ingredients. Utilization of a novel excipient, an inactive ingredient that has not been used in an approved drug product for the specified route of administration, will not only require comprehensive chemistry, manufacturing and control (CMC) information in the marketing application of the drug product containing the excipient, but will also likely require demonstration of safety of the excipient. Once an inactive ingredient has appeared in an approved drug product for a particular route of administration, the inactive ingredient is not considered new and may require a less intensive regulatory review the next time it is included in a new drug product.
While FDA-specific regulatory considerations are discussed, besides specific differences in filing mecha-nisms or scope for formulation changes during clinical development or after commercial licensure, similar regulatory principles and implications of formulation changes can be applied to other worldwide health authorities.
Conclusions
Modification of the pharmacokinetic profile of a drug and use of a pharmacodynamic-modulating agent in the formulation are two approaches with the potential of minimizing toxicity of orally administrated drugs. The pharmacokinetic modulating approaches employ various formulation techniques to modify the PK pro-file, while the pharmacodynamic modulating approach requires knowledge of the specificity of a drug’s biological
or pharmacological interaction with other compounds and understanding of the drug’s metabolic pathways.
Clearly, developing an optimized formulation that exhibits the optimal stability and delivers the required biological performance is a complex undertaking. Successful formulation development will require an adequate understanding of a drug’s physicochemical, biological, and safety properties. In addition, it requires effective cross-functional communication and collabo-ration, in-depth knowledge of specific disease states, and the ability to efficiently navigate within complex regula-tory requirements and constraints.
Acknowledgment
The authors are deeply thankful to Dr. Elizabeth Vadas (InSciTech Inc.) for her insightful feedback and guidance on this manuscript.
Declaration of interest
The authors report no conflicts of interest.
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Pharmaceutical Development and Technology
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