The art and science of drug titration

Drug titration versus dose adjustment

Drug titration may be based on PK/PD parameters, achievement of therapeutic outcomes, results of pharmacogenetic testing (PGT), and/or maintenance of drug safety.^2,3,17 It is important to keep in mind the distinction between drug titration and dose adjustment. A dose adjustment is necessary to maintain appropriate drug concentrations despite alterations in PK/PD parameters due to innate or external factors such as age, body weight (actual, ideal, or adjusted), drug interactions, metabolism, plasma protein binding, or renal/hepatic impairment.^2,3 Dose adjustment recommendations can be found in prescribing information and usually occur without a titration. For example, the dose of intravenous ciprofloxacin for an adult patient with chronic renal failure on hemodialysis is 400 mg every 24 h as compared with a dose of 400 mg every 12 h when a patient’s creatinine clearance (Cl_cr) is >30 ml/min for most infections.^18,19 The recommended dose of rimantadine for influenza A prophylaxis in the elderly is 100 mg orally daily (as opposed to twice daily), and the high-dose influenza vaccine is specifically approved for patients 65 years and older.^20,21 The administration of efavirenz and voriconazole concurrently is an example of a dose adjustment based on a drug–drug interaction. Efavirenz [always administered in combination with other antiretrovirals to provide a complete human immunodeficiency virus (HIV) regimen] is adjusted down to 300 mg/day orally when it is administered simultaneously with voriconazole, and the voriconazole dose is increased to 400 mg orally every 12 h.²² Lastly, ethambutol illustrates a dose adjustment based on weight: for patients weighing 40–55 kg, the recommended daily oral dose is 800 mg, for patients weighing 56–75 kg, the dose is 1200 mg, and for patients weighing 76–90 kg, the dose is 1600 mg.²³

Drug titration, in the traditional, scientific sense, is a change in dosing based on a specific PK/PD, clinical, pharmacogenetic, or laboratory parameter, or is based on a set titration schedule as per the prescribing information. It is dosing that is individualized to the specific patient, with the goal of reaching a specific laboratory or clinical target with the lowest dose possible, while mitigating adverse effects, and/or preventing withdrawal/discontinuation symptoms or disease recurrence. It may be accomplished via up-titration (increasing the dose over time), down-titration (decreasing the dose over time), or cross-titration (decreasing the dose of one drug while at the same time increasing the dose of another drug).³ A classic example of titration is the dosing of aminoglycosides and vancomycin based on therapeutic drug concentrations. In general, gentamicin is dosed based on ideal body weight, starting with a loading dose of 1.5–2 mg/kg intravenously, followed by 1–1.7 mg/kg (3–5 mg/kg/day) every 8 h with subsequent dose adjustments based on peak and trough concentrations and the minimum inhibitory concentration (MIC) of the bacterial pathogen.⁸ The goal is to maximize the peak concentration to MIC ratio (⩾8:1–10:1) to optimize bacterial killing.²⁴ Vancomycin is dosed based on actual body weight, starting with a loading dose of 20–35 mg/kg in critically ill patients, followed by 15–20 mg/kg/dose every 8–12 h with subsequent dose adjustments based on the ratio of the area under the curve (AUC) to the MIC of the bacterial pathogen.⁹ The aim of this dosing strategy is to sustain an AUC/MIC ratio of 400–600 for methicillin-resistant Staphylococcus aureus infections to have the best chance of clinical treatment success with decreased potential for nephrotoxicity.⁹ Further, PGT plays a role in tailoring both drug selection and dosing with the intent of optimizing effectiveness and minimizing adverse effects.¹⁷ PGT has been shown to be potentially helpful in these respects with anesthestics, anticonvulsants, antidepressants, antineoplastics, antiretrovirals, attention deficit hyperactivity disorder (ADHD) medications, mood stabilizers, and warfarin.^17,25–31

The art versus science of drug titration

The scientific principles of drug titration are to give the patient adequate and effective treatment, at the lowest dose possible, with the aim of minimizing unnecessary medication use and side effects.^2,3 The art of drug titration involves the interplay of scientific drug titration principles with the clinical expertise of the healthcare provider, and an individualized, patient-centered partnership between the provider and the patient to review the delicate balance of perceived benefits and risks from both perspectives. The art therefore takes into consideration what is realistic for a particular patient, including the intended therapeutic outcomes and management of drug titration based on each patient’s unique circumstances. This is an individualized approach that includes compromise and recognizes the patient’s autonomy, and evaluates the impact of positive and negative clinical outcomes, not just PK/PD and laboratory measurements. The patient factors that should be taken into account during the decision-making process may include, but are not limited to, the titration complexity, the patient’s expectations related to drug effectiveness and when therapeutic outcomes should occur, the severity of the disease, co-morbidities, concurrent medications, consequences of non-adherence, potential for and seriousness of adverse effects, personal priorities, health literacy, and socioeconomic status. These factors inherently influence a patient’s willingness to adhere to a drug titration schedule, without which the benefits of the medication will not come to fruition.^3,32–35 Artistry, rooted in scientific evidence, is used to select the most appropriate titration schedule for an individual patient, in particular when multiple strategies exist or strategies are less well-defined.

Evidence

Drug titration is a form of personalized medicine.² There is mounting evidence that substantial treatment heterogeneity exists in both clinical trials and real-world practice. This contradicts the notion that all patients being treated with a specific medication actually take the same dose, for the same duration, and in combination with the same concomitant medication(s).^61–63 While it is becoming clearer that a “one-size-fits-all” approach is not optimal for drug dosing,¹⁷ clinical trials with titrated medications are complex, as comparisons between fixed-dose and dose-titration or between various dose-titration schedules, are difficult to study. Such challenges include the maintenance of blinding, external validity, and increased potential for post-randomization biases (i.e., differential loss to follow up, differential adherence, and differential discontinuation).

In addition, it is difficult to establish real-world evidence for titrated medications. When patients do not have the same drug exposures (drug, dose, duration, and concomitant medications), it is difficult to attribute specific clinical outcomes to specific exposures. This challenge has been described in infectious diseases, in which it was found that treatment heterogeneity is nearly universal in bloodstream infections.⁶² Unfortunately, there is a lack of real-world exposure data for titrated medications, as data sources lack titration details. As a result, it is difficult to substantiate titration schedules, in terms of safety or effectiveness, since supportive data are unavailable. Therefore, drug titration complicates our understanding of the effect of medications in real-world practice.

Due to the lack of real-world evidence for titrated medications, clinicians often must rely on data from clinical trials to inform their prescribing of schedules for drug titration, despite the aforementioned clinical trial limitations. However, it is unclear whether titration schedules closely reflect titration from clinical trials and/or labeled titration, and some evidence suggests not only wide variation in titration schedules in clinical practice, but also divergence in titration schedules from clinical trials.⁴³ For instance, a meta-analysis determined that, out of 11 randomized clinical trials and 38 cohort studies of methylphenidate for the treatment of ADHD in children, only 2 and 8, respectively, reported their justification for the dose range used in the study.⁶⁴ However, the justification was either unclear or did not match the cited source in most of these studies, highlighting the lack of evidence supporting titration schedules of methylphenidate in ADHD. In addition, there was a wide variation in the dose titration as the dose in the randomized clinical trials ranged from 20 to 72 mg/day, whereas in the cohort studies, it ranged from 20 to 60 mg/day.⁶⁴ Also, in patients on medications for heart failure, it was found that the up-titration schedules carried out in clinical trials by dedicated research staff are not mirrored in the real-world setting, where lower doses are generally prescribed in contrast to the higher doses achieved in clinical trials.⁶⁵

Consensus

There may be a lack of consensus on titration schedules that maximize benefits and minimize harms,^3,49 or a lack of consensus on the therapeutic and toxic concentration of the medication.^3,11 One example of a drug that has indication-based titration schedules is quetiapine. The initial dose and dose increases for the titration are dependent on whether the drug is being used for schizophrenia, bipolar mania, or bipolar depression.¹⁴ Antiepileptic drugs demonstrate variability in therapeutic versus toxic drug concentration ranges. Some patients may experience seizure freedom at concentrations that are below the defined reference range, while others may have a reduction in seizures only when the concentrations are above the range, thus suggesting that each patient has his or her own individual target concentration.¹¹ This highlights that, although there may be a recommended titration schedule stemming from a “one-size-fits-all” approach based on prescribing information or clinical guidelines, providers may need to craft a titration regimen to best fit the needs of an individual patient.

The benefits of up-titration to attain a specific response with certain medications has been uncertain. In 2002, the recommendation for patients undergoing elective noncardiac surgery per the American College of Cardiology/American Heart Association Guideline for Perioperative Cardiovascular Evaluation for Noncardiac Surgery was to prescribe a beta-blocker days or weeks before surgery and titrate the dose to achieve a heart rate of 50–60 beats/min.⁶⁶ However, in the 2014 guideline update, the recommendation was modified as the benefit of starting beta-blockers in naïve patients prior to surgery was called into question along with how to titrate them in this setting.⁶⁷ Such uncertainly also exists with tapering (down-titrating) antidepressants. While some clinicians suggest decreasing the dose by 25% per week until the antidepressant is discontinued, others recommend decreasing the dose by 25% per month.⁵⁹ The protocol for benzodiazepine down-titration is also not well defined, as the recommendations range from decreasing the dose by 50% each week to decreasing it by 10–25% every 2 weeks.⁶⁰ Lastly, there may be an inability to measure objective outcomes without a specific marker for efficacy, effectiveness, or toxicity.²

Adherence

Further complicating the effectiveness and safety of drug titration is the inconvenience to the patient, which can impact medication adherence, including under-dosing (delay or failure to increase dose), over-dosing (initial high dose or rapid dose increases), and/or missed dosing. Drug titration is also inconvenient in terms of healthcare-related visits for dose titrations and/or monitoring.¹ Up to half of patients are non-adherent to their chronic medications, without taking into account the additional challenges surrounding dose titration,^3,68 and non-adherence is associated with harmful health consequences and increased healthcare costs.^17,35 As described earlier, patients may not take their medications or may not take them as prescribed, for numerous reasons, which includes complex regimens and adverse effects.^3,35

Starter kits and dose packs, such as those mentioned previously for lamotrigine and methylprednisolone, help to facilitate adherence to specific drug titration schedules.^{3,35,48,54,55} Titration packs are convenient for the provider and the patient, making it easier to adhere to a titrated regimen. However, they may not meet the needs of all patients, and, in some cases, may inadvertently cater to a “one-size-fits-all” approach and interfere with personalized dosing.^54,55

Although drug regimen complexity is recognized as a risk factor for non-adherence with certain medications, up-titration or down-titration also alleviates adverse effects, as has been described with antidepressants and anticonvulsants, potentially leading to improved adherence by reducing treatment interruptions or discontinuations.^{12,38,49,69–71} The need to coordinate care among providers and between providers and patients becomes more critical with drugs that require titration, both to monitor for effectiveness (or lack thereof) and adverse effects and to facilitate dose titration.^3,65 However, clinicians have limited time, inadequate support structures, and unclear roles regarding drug titration.⁶⁵

The complexities of drug titration affecting medication adherence are further complicated by multi-morbidity. Overall, medication utilization rates have increased over time, due to increases in available medications on the market to treat diseases (e.g., medications for certain conditions were not previously available), as well as increased rates of chronic diseases due to the changing health and life expectancy of the population (increase in chronic diseases such as diabetes, high blood pressure, high cholesterol, and greater multi-morbidity in aging populations). Data from the 2010 National Health and Nutrition Examination Survey (NHANES) found that approximately 39% of people who are at least 65 years of age were taking at least five prescription medications.⁷² Patients taking complex medication regimens have been shown to have worse medication adherence and patient outcomes. The addition of medications requiring titration adds further complexity to medication regimens for patients, making it more difficult to understand the dose and schedule, and, in turn, can reduce patient adherence.^1,3,35

Various strategies have been deployed to improve and support drug titration in clinical practice. A multidisciplinary healthcare approach can help improve the quality of medication titration. In the setting of heart failure, clinician education, decision support and communication tools, post-prescribing telephone monitoring of patients, auditing of clinicians, transitions of care and disease management services, and expanded prescribing privileges for nurses and pharmacists have been used to enable a more individualized approach to pharmacotherapy.⁶⁵ In addition, nurse-led titration services of heart failure medications have achieved target doses sooner while decreasing heart failure-related hospital admissions and increasing patient survival.⁷³ Multidisciplinary teams that combine elements of the above-described approaches that take into account the best fit for the specific clinical practice site are more likely to be successful.⁶⁵ Several studies have shown that pharmacist run titration services for insulin in patients with diabetes mellitus have resulted in improved glycemic control.^74,75 Similar programs utilizing pharmacists have been effective in the management of anticoagulation, neurologic conditions, and gout.^76–78 Appropriate drug titration that results in better patient outcomes may give rise to downstream cost savings. A study with PGT-guided therapy in bipolar disorder found a decrease in hospitalizations, a shorter duration of hospitalization, and less use of emergency medical services, ultimately leading to potential overall cost savings to the healthcare system, as compared with non-PGT guided therapy.⁷⁹

Involving patients in the treatment decision-making process can improve adherence, particularly when patient and provider expectations and responsibilities to each other are clearly established.³ With a collaborative approach, patients can take an active role in guiding their drug titrations. For example, a majority of adults with ADHD can identify when the effects of their medications are wearing off.⁸⁰ Providers can use this information to fine tune the drug titrations to improve symptom control over the course of the day.⁸⁰ Moreover, advances in information technology should allow both clinicians and patients to be partners in this individualized approach to drug dosing.¹ Information technology, for instance, electronic medical record systems, should assist in the collection and analysis of data from the real-world setting, which can then be used to inform clinical decision making for personalized medicine.¹⁷

Costs

Medication titration is associated with excess healthcare resource utilization and healthcare costs. One study from a nationwide panel of neurologists showed that, for patients utilizing antiepileptic drugs, periods of titration incurred higher healthcare resource utilization and costs compared with maintenance periods.⁸¹ Similarly, an analysis of a large claims database found that for patients with major depressive disorder who initiated therapy with a serotonin reuptake inhibitor, those who underwent dose titration experienced significantly higher healthcare resource utilization and healthcare costs after 8 weeks of therapy compared with those who did not undergo titration.⁸²

While PGT has the potential to reduce titration-associated cost, some important factors to consider for PGT are: who and when to test, which test to select, and how to interpret and use the test’s results.^27,83 For certain conditions, providers may consider PGT to provide minimal clinical information, and, therefore, not worth the costs.^27,83 Another barrier facing more widespread utilization of PGT in the United States is that third party payer reimbursement is highly variable depending upon the plan, the type of testing, and the specific test.^83–86 Due to this, if PGT is not covered by insurance, it is not likely patients will pay out-of-pocket for the service, with a survey showing that almost half of patients would not pay any out-of-pocket costs for PGT.⁸⁷

Titration can also lead to medication waste, as dose changes may require different prescriptions for different strengths and thus lead to leftover drug supply.^88,89 Further, insurance plan policies present a barrier to titration due to drug supply requirements. For example, the 30- or 90-day supply requirement for coverage of the prescription, despite titration occurring in shorter intervals, leads to an excess of medication being dispensed to the patient.^89,90 A complication of this excess supply, as observed with opioids and ADHD medications, is the potential for drug misuse or diversion.^91–94 Titration can also lead to prescription refill issues. There is the potential for delay in therapy when the up-titration quantity exceeds therapeutic quantity limits for lower doses. In addition, up-titration with an existing prescription, as instructed by a provider directly to a patient, presents challenges at the time of refill since, without knowledge of the up-titration, insurance will consider it an early fill and deny coverage.^95–98

Excess costs due to healthcare utilization and prescriptions fills, and corresponding drug waste, represent opportunities for improvement in drug titration. Insurance companies should devise procedures and policies that support optimization of drug titration. Further, increased acceptance of telehealth could support healthcare visits specifically for titration, thus reducing associated healthcare costs of titration-related visits from both a health system perspective, as well as direct and indirect patient costs.