Q&A with Lonza: Improving bioavailability across drug compounds
EPM speaks to Dan Dobry, director, head of Commercial Development, Small Molecule Drug Product at Lonza to learn about how to ensure good bioavailability across compounds and which therapy areas are benefitting from targeted drug delivery.
Q: How do you ensure good bioavailability across such a differing range of compounds in pharma?
A: The key to improving bioavailability across a range of compounds with differing physical-chemical properties is to strategically choose the best technology for each compound. At Lonza, we use a science-based approach to determine the mechanism of poor bioavailability along with bulk-sparing methodologies that allow each technology to be evaluated in vitro. This approach is based on learnings gained from screening thousands of molecules and progressing hundreds to clinical development or commercial production.
Q: What are the most common causes of poor bioavailability?
A: The primary causes of poor bioavailability are encompassed in the biopharmaceutical classification system quadrant II (BCS II). The two most common reasons for poor bioavailability for compounds in this quadrant are slow dissolution rate (DCS IIa) and low solubility (DCS IIb). These two causes constitute around 50%-70% of poorly bioavailable compounds. Additionally, some 10%-20% of the compounds are poorly permeable. These compounds fall into either BCS Class III (high solubility/low permeability) or BCS Class IV (low solubility/low permeability).
Q:What technologies are pharma companies using to improve bioavailability?
A: There are myriad technologies that have been developed for improving bioavailability. However, the three most common technologies used for commercially-viable compounds are particle size reduction (jet milling), lipid-based formulations (SEDDs) and amorphous solid dispersions (ASDs). ASD formulations are manufactured using either spray drying or hot-melt extrusion depending on physical-chemical properties. Jet milling/particle size reduction increases bioavailability of compounds that have slow dissolution rates while keeping the compound in the crystalline state. In contrast, SEDD formulations enhance solubility by dissolving the compound in a lipid solution or suspension encapsulated in a capsule or softgel format. The SEDD then forms into nanometer-sized droplets when the drug is administered to the patient. ASDs trap the compound in an amorphous form that is more readily dissolved than the crystalline state, and also often provides sustained solubility via use of colloidal polymers or surfactants.
Q: How ineffective can a drug become when the compound displays low solubility, bioavailability or dissolution?
A: A compound that has a slow dissolution rate or poor solubility can become completely ineffective if absorption in the gut is minimal. Most often the consequence is high variability, especially for therapies with a narrow therapeutic window. This outcome can lead to failed efficacy in some patients or requirements for restrictive labels such as foods or antacid therapies. In a worst-case scenario, a poorly bioavailable/unabsorbed drug can have a negative impact on the patient due to off-target toxicities of the unabsorbed drug in the gut.
Q: In terms of targeted drug delivery which disease areas are benefitting the most from this method?
A: Oncology and inflammation are two disease areas that are benefitting from targeted delivery. This is primarily because compounds being developed are often not specific to a single biological target in the oncology or inflammatory cascades, leading to potential off-target activity. Targeted delivery directs the drug to the desired biological target, increasing its efficacy. In addition, local targeting such as inhaled delivery by particle engineering, or lower gastrointestinal (GI) targeting with modified release formulations can ensure the drug is physically placed at the desired point of action.
Q: Do the products used for targeted drug delivery or to increase bioavailability affect the way patients take their drugs?
A: Generally, methods for increasing bioavailability or targeting do not change the way patients take their drugs. In pharma drug delivery, the oral route remains the preferred route of administration. Amorphous solid dispersions, which are used in over 25 commercial products, are generally delivered via the oral route as a tablet or in a capsule.
Q: More so, what considerations does Lonza take about the patient when developing new products or methods to improve drug delivery?
A: Patient-centricity is central to Lonza’s approach in developing and deploying drug delivery technologies. It is one of the first factors accounted for when developing the target product profile (TPP) for a new medicine. Whether it is minimising tablet size by using our high-loaded dosage form format for amorphous solid dispersions (ASD) or a coated lipid multiparticulate (LMP) for taste-masking, the patient’s needs are always a priority.
Q: Biologics are currently limited to intravenous delivery only due to the sensitive nature of the gastrointestinal (GI) area. Do you anticipate this changing towards oral routes as therapies progress?
A: Biologics, due to their large size/high molecular weight, are poorly permeable in the gut and can be readily degraded by the low stomach pH or gut enzymes. While there are a number of ongoing efforts to deliver biologics orally and even a recent product approval (Rybelsus, semiglutide) the current efforts remain plagued by low oral bioavailability, generally in the low single digit range. Other exceptions can be found in local targeting. Some biologics are intended to act in the lower GI or the lung, enabling potential formulation with oral or inhaled forms. While it is a noble effort to deliver biologics orally, most biologics will likely remain injectable products for the foreseeable future to maximise cost effectiveness and patient compliance.