Co-crystallization: a Tool to Tune the Pharmacokinetic Profile of Drugs
September 20, 2023
This blog is based on the article “Celecoxib-tramadol co-crystal: A Randomized 4-Way Crossover Comparative Bioavailability Study” that investigates the pharmacokinetic profile of a co-crystal drug and compares it to its single components.
The article was published in Clinical Therapeutics and can be accessed here.
Acute pain is a common multifactorial medical condition that affects a high percentage of postsurgical patients and patients admitted to emergency departments. If not treated appropriately, acute pain can have a considerable impact on a patient’s life, and in some cases progress to chronic pain.
The most effective way to treat acute pain is through a pharmacologic approach targeted to the specific cause of pain. The treatment should be started as early as possible and using multimodal analgesia, a combination of analgesic medications with complementary mechanisms of action. This work aimed to investigate this approach via the administration of a co-crystal drug, a compound that contains two or more active substances.
Celecoxib-tramadol co-crystal (CTC) is composed by two approved analgesics, celecoxib and racemic tramadol hydrochloride, in a 1:1 molecular ratio. This novel drug is under development by ESTEVE Pharmaceuticals in Barcelona (Spain), and it is hypothesized to provide multimodal analgesia through the synergy or addition of the analgesic actions of its components.
In this work, the pharmacokinetic (PK) profile of the CTC is compared to the one of the two components celecoxib and tramadol, both taken alone and simultaneously. Additionally, the safety and tolerability of the CTC is investigated.
Subjects and Methods
The study was performed in a clinical research centre in the United States, through the oral administration of 4 single dose treatments separated by a 7-day break.
Some inclusion and exclusion criteria were considered to select the sample of people. Adults in good health, both female and male, with an age between 18 to 55 years, non-smokers and with a body mass index between 18.5 and 32.0 kg/m2 were considered eligible for the study. Pregnancy, hypersensitivity to drugs, intake of high quantities of alcohol, drugs or blood donation within the previous 2 months were instead considered exclusion criteria.
Four different treatments were carried out on a rota system: CTC tablets only (Treatment 1, T1); racemic tramadol hydrochloride tablets only (Treatment 2, T2); celecoxib capsule only (Treatment 3, T3); racemic tramadol hydrochloride and celecoxib taken simultaneously (Treatment 4, T4). Full details about the dosage of each treatment can be found in the article.
PK measurements were performed analysing blood samples collected before and after drug administration, with particular focus on collecting plenty of samples to monitor the 24 hours after drug administration. The concentration of tramadol, O-desmethyl tramadol, and celecoxib were measured from the plasma samples using reversed-phase HPLC with MS/MS detection.
Results and Discussion
Initially, a total of 36 people took part to the study and received the first treatment. Three subjects were then excluded from the PK study due to withdrawal prior to the administration of the second treatment. 33 subjects provided hence data for at least 2 treatments.
The PK parameters were analysed to compare the PK profile of the CTC with the ones of the single components, tramadol and celecoxib. More specifically, researchers looked at the Cmax, defined as the peak plasma concentration of a drug after administration; “area under the curve”, abbreviated AUC, which is the integral of the concentration of a drug in blood plasma as a function of time; Tmax, which is the minimum time taken to reach the Cmax. Additional PK parameters can be found in the main article.
Researchers found that the drug celecoxib from the CTC presented a lower Cmax, reduced AUCs, and showed a faster Tmax when compared to the celecoxib taken alone, hence showing a faster drug absorption without increasing its systemic exposure. Additionally, the interference in celecoxib absorption is minimized with the CTC, while its absorption is inhibited when taken simultaneously with tramadol. It was hypothesised that the inclusion of celecoxib in the CTC may accelerate the absorption of the molecule that, by itself, is poorly soluble.
Similarly, tramadol and tramadol’s active metabolite O-desmethyl tramadol from the CTC presented lower Cmax and AUCs, with a slight extension of Tmax when compared to the tramadol drug taken alone or administrated with celecoxib. The latter is due to the fact that the CTC structure synchronizes the release of both the co-crystal constituents.
From the presented results it can be seen that the use of celecoxib-tramadol co-crystal, CTC, optimised the PK profile of the two single components, leading to lower Cmax and longer Tmax for tramadol, and faster absorption of celecoxib, without increasing their systemic exposure.
Finally, fewer adverse events (AEs) were reported when tramadol was administered with the CTC compared to when it was taken alone or co-administrated with celecoxib.
The use of co-crystals to modulate and improve the physicochemical properties of drugs is still an area that requires developments. Furthermore, it is difficult to predict whether two APIs will co-crystallize, as this is highly dependent on their chemical structures.
The results seen with celecoxib-tramadol co-crystal are, however, very promising. The use of CTC led to more favourable PK profiles when compared to the ones of the single components celecoxib and tramadol, without resulting in an increasing exposure level of any of the two APIs. These differences are likely influenced by the crystalline structure of the CTC, further highlighting the importance of the structural investigation of co-crystal drugs.
Read the blog “CSD Molecular Complementarity Tool Domain of Applicability“.
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