Exploring what lies under the “sub-dose”

Disclaimer:

This article is for the purpose of CME and gaining experience as a medical writer. After reviewing and analyzing selected studies and trials, the author's conclusions are based on her perspective as a researcher and healthcare professional. The articles have not been reviewed by another party. Any error or copying is due to human error and is unintentional.

?

Abstract:

The article is a mini-review, going over the subject of correct drug dosing, starting with the basic principles, briefly explaining the significance of dosing choice in both research and clinical settings, then exploring evidence relating to the controversy surrounding the use of sub-therapeutic dosing and its possible implication.

Method:

Key words were utilized to find evidence-based answers to questions developed about the use of suboptimal doses of drugs. MDPI, PUBMED, NIH, NCB, SPRINGERLINK, and ELSEVIER data bases were used to find clinical studies, article reviews, prospective and retrospective studies, meta-analyses, and research model proposals. The information reviewed was summarized and organized to compose this article.

Article:

Correct dosing is essential for a drug to achieve its optimal intended effect following administration with as little harm as possible to the patient’s overall health and quality of life, which can include the expenses of taking a drug in vain or with no effect on the indication it was prescribed for. (Tyson et al., 2020a) (Grogan & Preuss, 2022). (Tan et al. (2022)) conducted a cross-sectional study to estimate pediatric medication errors in multi-primary care settings and discovered that dosing errors, which included both over- and under-dosing, accounted for 27% of the reviewed pediatric prescriptions after they met their inclusion criteria, and were the most common type of error in their study.

Dose finding is usually assigned to phase I clinical trials, focusing on determining the safety, giving the maximum tolerated dose of the drug without serious side effects (NCI Dictionary of Cancer Terms, 2011), and the recommended dose to be given (Ursino et al., 2017). Drug efficacy, on the other hand, is not evaluated until phase II clinical trials, which are the usual sources of pharmacodynamic biomarkers (Ursino et al., 2017).As important as the interaction between the drug and its receptor or target is, keeping in mind the pharmacokinetics’ available data regarding drug metabolism and distribution from both clinical and pre-clinical studies is critical (Grogan & Preuss, 2022; Derendorf et al., 2000; Glassman & Muzykantov, 2019a), especially for dose-justification data required by the regulatory authorities. (Ursino et al., 2017) (Mould & Upton, 2012; J?nsson et al., 2012).

?(Ursino et al., 2017), had addressed the incorporation of PK measurements in dose-finding designs to revamp dose-choice recommendations for the following trials.

Choosing a dose in the drug development process is of great importance. It’s neither acceptable to choose a too high nor a too low dose. Identification of the minimum statistically significant and biologically or clinically effective dose is by means of dose-response data analysis (Bretz et al., 2005). Which is typically addressed in phase II clinical study, it’s significance appears in drugs with positive correlation between toxicity and increasing the dose (Thomas & Ting, 2007). Selecting a too low dose for clinical trials can lead to a failed program due to the inadequacy of the effect in confirmatory studies (Bretz et al., 2010). It is thought that even if a study design is reliable enough to estimate the target doses of the trial with relativity and precision, it’s still rarely applied in clinical practice (Bretz et al., 2010). The study that determines the best dose for the drug is usually referred to as a "dose escalation study," where the goal is to reach the maximum tolerated dose. It can also elaborate on how the drug is utilized by the body, and it’s mostly a part of a phase I clinical trial. (Definition of Dose-Escalation Study, NCI Dictionary of Cancer Terms, NCI, 2011) The goal of dose escalation in phase I clinical trials?includes giving the patients in the phase II clinical trial a treatment dose within the therapeutic range that is effective and safe, avoiding a sub-therapeutic dose, which can be troublesome regarding the unnecessary exposure of the patients to ineffective medication, especially in cancer clinical trials (Le Tourneau et al., 2009). (Le Tourneau et al., 2009) provided a review of various dose escalation methods in cancer phase I clinical trials, focusing on their application to molecularly targeted agents. It should be noted that only controlled-randomized trials can validate a relationship between pharmacodynamic biomarkers and clinical outcome?(Le Tourneau et al., 2009).

?

The maximum tolerated dose is the one used in subsequent studies, especially in oncology (Sleijfer & Wiemer, 2008). Which had raised an alarm to propose ?the “very- low dose approach” by (McCormack et al., 2011), using evidence of post marketing dose reduction as part of their rationale(Postmarketing Drug Dosage Changes of 499 FDA-Approved New Molecular Entities, 1980-1999 - PubMed, n.d.), attributing the increase in dose adjustment to investigating the drug at the (MTD) in phase III trials.

Another investigational implication of sub-therapeutic dose (with pharmacological effect) is its use in phase 0 of an exploratory investigational new drug clinical trial to better evaluate the drug's target modulation and assay, to differentiate the drug molecule from other candidates to continue with in subsequent phases, and even for PK/PD assessment, all in order to address some of the challenges in oncology research (Kummar et al., 2007).

(McCormack et al., 2011a)?have proposed that most conditions, including chronic ones seen in general practice, rarely require an immediate response to treatment, advocating for the ” very-low dose approach”. ?However, in a disease like cancer, this cannot be acceptable. In oncology, the concept of "the more, the better" in an escalating study was extrapolated from preclinical model results. (Sleijfer & Wiemer, 2008).

?(Tyson et al., 2020a) stated that a suboptimal dose of a drug can not only decrease its efficacy but also cause poor safety-related outcomes. (Gonzalez et al., 2017) in their argument about the consequences of imprecise dosing, they have elaborated on the worrisome effects of sub-dosing due to inter-patient diversity whilst receiving a drug dose that evidently achieves efficacy within the therapeutic range ( (standard dosing recommended for the indication based on controlled randomized- clinical trials(Tyson et al., 2020b)). Such dose can reach a maximal effect only if it is not affected by factors like differences in body weight, patient adherence, or metabolizing enzyme induction, and have stated that suboptimal dosing can lead to an unwanted outcome. They used transplant rejection (Graft Vs Host disease as an example for the conditions where sub-optimal dosing can be life threatening. (Gonzalez et al., 2017)

(Tyson et al., 2020b) have discussed variables that should be kept in mind when prescribing the labeled standard dose regimen to certain categories of patients who might benefit more from a tailored precision dosing approach. Some of the variables are drug-related; others are related to disease state and pharmacogenomics, among other variables they have discussed as precision dosing candidature evaluating factors. Moreover, some conditions, like advanced liver disease, can lead to faulty prescription of drug doses due to advanced changes in PK and PD (Delc et al., 2005) along with changes in physiology and architecture (Garca-Cortés & Garca-Garca, 2022). A bias toward under-prescribing drugs was discovered in one study (Lucena et al., 2002). Additionally, under-filling of appropriate medication in patients with hepatic advanced disease was observed in a study by (Thomson et al., 2021), which could indicate the need for training and a lack of an established, evidence-based strategy to prescribe medications for this type of condition, possibly even a scarcity of evidence that could affect other conditions similarly. On the other hand, reduction of the initial dose of oral drugs with high hepatic extraction is recommended in cirrhotic patients (Delc et al., 2005).

(McCormack et al., 2011b), provided evidence that sub-dosing in comparison to the standard dose recommended by a controlled randomized trial can be rational because the marketed dose is "irrationally high" and in fact the placebo effect of a minimal drug dose was argued to be advantageous (Hróbjartsson & Gtzsche, 2004), they have supported their “very-low-dose” approach using evidence based on clinical trials that found no difference in effect. One of them combined low-doses of two drugs and demonstrated clinically relevant effects with less adverse events (Frishman et al., 1994) Another one showed only a statistically significant difference from placebo but not a clinically relevant one with one of the doses, while doubling that dose showed significance in both with lower adverse drug events, even comparable to placebo (Ka et al., 1999). Some of the limitations they have mentioned in their approach included acute life-threatening conditions, conditions where under dosing will be dangerous in accordance with (Gonzalez et al. (2017), idiosyncratic allergic reactions that are not dose-related, and a lack of evidence on the effect of lower doses of some drugs, among others.

Elaborating more on sub-dose efficacy’s evidence, a sub-anesthetic dose of 0.1 mg/kg dextro-ketamine induced enough sedation to get the patient comfortable in order to facilitate the block with a 21G needle in more than half of the patients with hemodynamic changes, which was the lowest dose of the four compared sub-anesthetic doses. (Imbellon et al., 2017). In a study by (Guo et al. (2011), a sub-dose of the selective ROCK inhibitor, fasudil, in uninephrectomized Sprague-Dawley rats (SD), showed significantly improved myocardium hypertrophy and fibrosis, showing a cardio protective effect of this sub-dose. (Ribeiro et al., n.d.), demonstrated that the human chorionic gonadotropin’s dose usually prescribed for ovulation induction in donkeys is too high by administering a sub-dose that showed sufficiency, when administered at the false acupoint. A remarkably interesting study indicated that the sub-dose anti-seizure effect could be enhanced using long-term adjuvant music therapy (Xu et al., 2022). Furthermore, a sub-anesthetic dose of ketamine reduced post-operative depression as well as cancer stem cell markers' serum levels like IL6 in colorectal cancer patients; it's worth noting that the dose demonstrating this significant effect was the highest of three compared sub- anesthetic doses (0.3 mg/kg) (Ren et al., 2022).

?

According to the FDA, an example of "off-label" unapproved drug use is the use of a different dose of the same approved drug (Commissioner, 2019). It’s a common practice in the pediatric population to administer drugs for off-label use, according to (Oshikoya et al. (2019). (Knopf et al., 2013) (Belayneh et al., 2022)

(Knopf et al., 2013) also stated that under-doing frequency necessitates more attention in order to spare patients the exposure to side effects without any benefit from the medication, and that more research into the underlying causes of such prevalence is required, including knowledge of health care professionals (consistently with the findings of (Belayneh et al., 2022), care provider awareness, and the practicability of pediatric therapeutics.

?

Comment and conclusion:

Sub-dosing of therapeutic drugs is a common practice, it can be necessary, and it can be fatal. It goes without saying that the main principles of pharmacokinetics and pharmacodynamics, as well as reliable scientific evidence, inter and intra-patient variations, and formulation variability (Hatton et al., 2019), (Borowy & Ashurst, 2022), (Glassman & Muzykantov, 2019b) should be kept in mind when the situation requires sub-optimal dose administration. Further evidence is still highly needed to fill the gaps of sub-populations and context variability between studies showing positive effect of sub-optimal dose and clinical practice.

?

Bibliography

?

Belayneh, A., Abatneh, E., Abebe, D., Getachew, M., Kebede, B., & Dessie, B. (2022). Off-label medication use in pediatrics and associated factors at public hospitals in east Gojjam zone, Ethiopia. SAGE Open Medicine, 10, 20503121221096536. https://doi.org/10.1177/20503121221096534

Borowy, C. S., & Ashurst, J. V. (2022). Physiology, Zero and First Order Kinetics. In StatPearls. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK499866/

Bretz, F., Dette, H., & Pinheiro, J. (2010). Practical considerations for optimal designs in clinical dose finding studies. Statistics in Medicine, 29(0), 10.1002/sim.3802. https://doi.org/10.1002/sim.3802

Bretz, F., Pinheiro, J. C., & Branson, M. (2005). Combining multiple comparisons and modeling techniques in dose-response studies. Biometrics, 61(3), 738–748. https://doi.org/10.1111/j.1541-0420.2005.00344.x

Commissioner, O. of the. (2019, April 18). Understanding Unapproved Use of Approved Drugs “Off Label.” FDA; FDA. https://www.fda.gov/patients/learn-about-expanded-access-and-other-treatment-options/understanding-unapproved-use-approved-drugs-label

Compressing drug development timelines in oncology using phase “0” trials—PubMed. (n.d.). Retrieved January 11, 2023, from https://pubmed.ncbi.nlm.nih.gov/17251919/

David, S., & Hamilton, J. P. (2010). Drug-induced Liver Injury. US Gastroenterology & Hepatology Review, 6, 73–80. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3160634/

Definition of dose-escalation study—NCI Dictionary of Cancer Terms—NCI (nciglobal,ncienterprise). (2011, February 2). [NciAppModulePage]. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/dose-escalation-study

Definition of maximum tolerated dose—NCI Dictionary of Cancer Terms—NCI (nciglobal,ncienterprise). (2011, February 2). [NciAppModulePage]. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/maximum-tolerated-dose

Delcò, F., Tchambaz, L., Schlienger, R., Drewe, J., & Kr?henbühl, S. (2005). Dose Adjustment in Patients with Liver Disease. Drug Safety, 28(6), 529–545. https://doi.org/10.2165/00002018-200528060-00005

Derendorf, H., Lesko, L. J., Chaikin, P., Colburn, W. A., Lee, P., Miller, R., Powell, R., Rhodes, G., Stanski, D., & Venitz, J. (2000a). Pharmacokinetic/pharmacodynamic modeling in drug research and development. Journal of Clinical Pharmacology, 40(12 Pt 2), 1399–1418.

Derendorf, H., Lesko, L. J., Chaikin, P., Colburn, W. A., Lee, P., Miller, R., Powell, R., Rhodes, G., Stanski, D., & Venitz, J. (2000b). Pharmacokinetic/pharmacodynamic modeling in drug research and development. Journal of Clinical Pharmacology, 40(12 Pt 2), 1399–1418.

Frishman, W. H., Bryzinski, B. S., Coulson, L. R., DeQuattro, V. L., Vlachakis, N. D., Mroczek, W. J., Dukart, G., Goldberg, J. D., Alemayehu, D., & Koury, K. (1994). A multifactorial trial design to assess combination therapy in hypertension. Treatment with bisoprolol and hydrochlorothiazide. Archives of Internal Medicine, 154(13), 1461–1468.

Frontiers | Effects of a Single Sub-Anesthetic Dose of Ketamine on Postoperative Emotional Responses and Inflammatory Factors in Colorectal Cancer Patients. (n.d.). Retrieved January 11, 2023, from https://www.frontiersin.org/articles/10.3389/fphar.2022.818822/full

García-Cortés, M., & García-García, A. (2022a). Management of Pharmacologic Adverse Effects in Advanced Liver Disease. Clinical Drug Investigation, 42(1), 33–38. https://doi.org/10.1007/s40261-022-01150-w

García-Cortés, M., & García-García, A. (2022b). Management of Pharmacologic Adverse Effects in Advanced Liver Disease. Clinical Drug Investigation, 42(1), 33–38. https://doi.org/10.1007/s40261-022-01150-w

Glassman, P. M., & Muzykantov, V. R. (2019a). Pharmacokinetic and Pharmacodynamic Properties of Drug Delivery Systems. The Journal of Pharmacology and Experimental Therapeutics, 370(3), 570–580. https://doi.org/10.1124/jpet.119.257113

Glassman, P. M., & Muzykantov, V. R. (2019b). Pharmacokinetic and Pharmacodynamic Properties of Drug Delivery Systems. The Journal of Pharmacology and Experimental Therapeutics, 370(3), 570–580. https://doi.org/10.1124/jpet.119.257113

Gonzalez, D., Rao, G. G., Bailey, S. C., Brouwer, K. L. R., Cao, Y., Crona, D. J., Kashuba, A. D. M., Lee, C. R., Morbitzer, K., Patterson, J. H., Wiltshire, T., Easter, J., Savage, S. W., & Powell, J. R. (2017). Precision Dosing: Public Health Need, Proposed Framework, and Anticipated Impact. Clinical and Translational Science, 10(6), 443–454. https://doi.org/10.1111/cts.12490

Grogan, S., & Preuss, C. V. (2022). Pharmacokinetics. In StatPearls. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK557744/

Guo, P., Wu, C., Masaki, T., Mori, H., & Nishiyama, A. (2011). Subdose of fasudil suppresses myocardial fibrosis in aldosterone-salt-treated uninephrectomized rats. Die Pharmazie, 66(9), 716–719.

Hatton, G. B., Madla, C. M., Rabbie, S. C., & Basit, A. W. (2019). Gut reaction: Impact of systemic diseases on gastrointestinal physiology and drug absorption. Drug Discovery Today, 24(2), 417–427. https://doi.org/10.1016/j.drudis.2018.11.009

Hróbjartsson, A., & G?tzsche, P. C. (2004). Placebo interventions for all clinical conditions. The Cochrane Database of Systematic Reviews, 3, CD003974. https://doi.org/10.1002/14651858.CD003974.pub2

Imbellon, L. E., Gouveia, M. A., & de Morais Filho, G. B. (2017). Comparison of the Effects of Four Subdoses of Dextroketamine to Reduce Pain during Posterior Brachial Plexus Block: A Randomized Double Blind Study. Anesthesia, Essays and Researches, 11(2), 345–349. https://doi.org/10.4103/0259-1162.186590

J?nsson, S., Henningsson, A., Edholm, M., & Salmonson, T. (2012). Role of modelling and simulation: A European regulatory perspective. Clinical Pharmacokinetics, 51(2), 69–76. https://doi.org/10.2165/11596650-000000000-00000

Ka, P., Wm, G., K, B., Je, P., Ee, G., Ma, S., & Aa, C. (1999). Low-dose ranitidine for the relief of heartburn. Alimentary Pharmacology & Therapeutics, 13(4). https://doi.org/10.1046/j.1365-2036.1999.00507.x

Knopf, H., Wolf, I.-K., Sarganas, G., Zhuang, W., Rascher, W., & Neubert, A. (2013). Off-label medicine use in children and adolescents: Results of a population-based study in Germany. BMC Public Health, 13(1), 631. https://doi.org/10.1186/1471-2458-13-631

Kummar, S., Kinders, R., Rubinstein, L., Parchment, R. E., Murgo, A. J., Collins, J., Pickeral, O., Low, J., Steinberg, S. M., Gutierrez, M., Yang, S., Helman, L., Wiltrout, R., Tomaszewski, J. E., & Doroshow, J. H. (2007). Compressing drug development timelines in oncology using phase “0” trials. Nature Reviews. Cancer, 7(2), 131–139. https://doi.org/10.1038/nrc2066

Le Tourneau, C., Lee, J. J., & Siu, L. L. (2009). Dose Escalation Methods in Phase I Cancer Clinical Trials. JNCI Journal of the National Cancer Institute, 101(10), 708–720. https://doi.org/10.1093/jnci/djp079

Lucena, I. M., Andrade, R. J., Tognoni, G., Hidalgo, R., de la Cuesta, F., & the Spanish Collaborative Study Group on Therapeutic Management in Liver Disease. (2002). Multicenter hospital study on prescribing patterns for prophylaxis and treatment of complications of cirrhosis. European Journal of Clinical Pharmacology, 58(6), 435–440. https://doi.org/10.1007/s00228-002-0474-1

McCormack, J. P., Allan, G. M., & Virani, A. S. (2011a). Is bigger better? An argument for very low starting doses. CMAJ : Canadian Medical Association Journal, 183(1), 65–69. https://doi.org/10.1503/cmaj.091481

McCormack, J. P., Allan, G. M., & Virani, A. S. (2011b). Is bigger better? An argument for very low starting doses. CMAJ : Canadian Medical Association Journal, 183(1), 65–69. https://doi.org/10.1503/cmaj.091481

Mould, D. R., & Upton, R. N. (2012). Basic Concepts in Population Modeling, Simulation, and Model-Based Drug Development. CPT: Pharmacometrics & Systems Pharmacology, 1(9), e6. https://doi.org/10.1038/psp.2012.4

Oshikoya, K. A., Wharton, G. T., Avant, D., Van Driest, S. L., Fenn, N. E., Lardieri, A., Doe, E., Sood, B. G., Taketomo, C., Lieu, P., Yen, L., & McMahon, A. W. (2019). Serious Adverse Events Associated with Off-Label Use of Azithromycin or Fentanyl in Children in Intensive Care Units: A Retrospective Chart Review. Pediatric Drugs, 21(1), 47–58. https://doi.org/10.1007/s40272-018-0318-9

Pharmacokinetic/pharmacodynamic modeling in drug research and development—PubMed. (n.d.). Retrieved January 10, 2023, from https://pubmed.ncbi.nlm.nih.gov/11185661/

Placebo interventions for all clinical conditions—PubMed. (n.d.). Retrieved January 11, 2023, from https://pubmed.ncbi.nlm.nih.gov/15266510/

Postmarketing drug dosage changes of 499 FDA-approved new molecular entities, 1980-1999—PubMed. (n.d.). Retrieved January 11, 2023, from https://pubmed.ncbi.nlm.nih.gov/12426927/

Price, G., & Patel, D. A. (2022a). Drug Bioavailability. In StatPearls. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK557852/

Price, G., & Patel, D. A. (2022b). Drug Bioavailability. In StatPearls. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK557852/

Ren, Q., Hua, L., Zhou, X., Cheng, Y., Lu, M., Zhang, C., Guo, J., & Xu, H. (2022). Effects of a Single Sub-Anesthetic Dose of Ketamine on Postoperative Emotional Responses and Inflammatory Factors in Colorectal Cancer Patients. Frontiers in Pharmacology, 13. https://www.frontiersin.org/articles/10.3389/fphar.2022.818822

Ribeiro, M. de O., Bittencourt, R. F., Feliciano, M. A. R., Santana, A. L. A., Silva, M. A. de A., Felix, M. D., Santana, L. R., & Barbosa, L. P. (n.d.). Subdose of human chorionic gonadotropin applied at the Hou Hai acupoint on follicular dynamics and luteal development in donkeys. Animal Reproduction, 17(4), e20200554. https://doi.org/10.1590/1984-3143-AR2020-0554

Sleijfer, S., & Wiemer, E. (2008). Dose Selection in Phase I Studies: Why We Should Always Go for the Top. Journal of Clinical Oncology, 26(10), 1576–1578. https://doi.org/10.1200/JCO.2007.15.5192

Tan, L., Chen, W., He, B., Zhu, J., Cen, X., & Feng, H. (2022). A Survey of Prescription Errors in Paediatric Outpatients in Multi-Primary Care Settings: The Implementation of an Electronic Pre-Prescription System. Frontiers in Pediatrics, 10, 880928. https://doi.org/10.3389/fped.2022.880928

Thomas, N., & Ting, N. (2007). Minimum Effective Dose (MinED). https://doi.org/10.1002/9780471462422.eoct316

Thomson, M. J., Lok, A. S. F., & Tapper, E. B. (2021). Appropriate and Potentially Inappropriate Medication Use in Decompensated Cirrhosis. Hepatology, 73(6), 2429–2440. https://doi.org/10.1002/hep.31548

Tyson, R. J., Park, C. C., Powell, J. R., Patterson, J. H., Weiner, D., Watkins, P. B., & Gonzalez, D. (2020a). Precision Dosing Priority Criteria: Drug, Disease, and Patient Population Variables. Frontiers in Pharmacology, 11. https://www.frontiersin.org/articles/10.3389/fphar.2020.00420

Tyson, R. J., Park, C. C., Powell, J. R., Patterson, J. H., Weiner, D., Watkins, P. B., & Gonzalez, D. (2020b). Precision Dosing Priority Criteria: Drug, Disease, and Patient Population Variables. Frontiers in Pharmacology, 11. https://www.frontiersin.org/articles/10.3389/fphar.2020.00420

Tyson, R. J., Park, C. C., Powell, J. R., Patterson, J. H., Weiner, D., Watkins, P. B., & Gonzalez, D. (2020c). Precision Dosing Priority Criteria: Drug, Disease, and Patient Population Variables. Frontiers in Pharmacology, 11, 420. https://doi.org/10.3389/fphar.2020.00420

Ursino, M., Zohar, S., Lentz, F., Alberti, C., Friede, T., Stallard, N., & Comets, E. (2017). Dose‐finding methods for Phase I clinical trials using pharmacokinetics in small populations. Biometrical Journal. Biometrische Zeitschrift, 59(4), 804–825. https://doi.org/10.1002/bimj.201600084

Xu, C.-L., Nao, J.-Z., Shen, Y.-J., Gong, Y.-W., Tan, B., Zhang, S., Shen, K.-X., Sun, C.-R., Wang, Y., & Chen, Z. (2022). Long-term music adjuvant therapy enhances the efficacy of sub-dose antiepileptic drugs in temporal lobe epilepsy. CNS Neuroscience & Therapeutics, 28(2), 206–217. https://doi.org/10.1111/cns.13623