Time to steady state with slow titration of vortioxetine drops versus oral tablets: a pharmacokinetic model

doi:10.21203/rs.3.rs-7023217/v1

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Time to steady state with slow titration of vortioxetine drops versus oral tablets: a pharmacokinetic model

https://doi.org/10.21203/rs.3.rs-7023217/v1

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published 30 Sep, 2025

Read the published version in Annals of General Psychiatry →

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Background

The antidepressant vortioxetine is available as an immediate-release (IR) tablet formulation and as a bioequivalent oral drops solution (20mg/mL) to allow personalised titration.

Methods

This pharmacokinetic modelling analysis used data from a single-dose, crossover study to simulate the time taken to reach steady-state plasma concentrations using ‘low and slow’ titration approaches with drops compared with standard IR-tablet schedules.

Results

All dosing regimens approached 10mg steady-state concentrations within 2 weeks. The time to reach full steady-state was 12 days when starting with a 10mg IR-tablet, 14 days when starting with 5mg drops and increasing to 10mg (1mg/day increments), 17 days when starting with a 5mg IR-tablet for 7 days before increasing to 10mg, and 18 days when starting with 1mg drops and increasing to 10mg (1mg/day increments).

Conclusions

These data support the utility of vortioxetine drops in offering flexibility for personalised titration without relevant impact on the time taken to reach steady-state plasma concentrations.

antidepressant

drop solution

major depressive disorder

pharmacokinetics

vortioxetine

Having a good titration experience has been shown to be important for long-term antidepressant medication adherence [1]. While side effects such as nausea and vomiting can be dismissed as “usually mild and transient”, a proportion of patients will find them intolerable and a cause for intermittent noncompliance with the prescription or discontinuation [2]. Certain types of patients including the elderly, frail and those with significant somatic comorbidities often benefit from the ‘start low and go slow’ approach which mitigates the appearance of those side effects (including nausea) linked to excessively fast increase of neurotransmitters [3]. However, the ability to do this depends on having flexibility of dosing options, which may be limited to certain tablet sizes.

Vortioxetine is a multimodal antidepressant indicated for the treatment of major depressive disorder (MDD) [4]. Currently approved at doses between 5 mg and 20 mg, it is available as an immediate-release (IR) tablet formulation in 5, 10, and 20 mg dose strengths (a 15 mg tablet is also available in certain countries) and as a bioequivalent oral drop solution of 20 mg/mL [5]. Whereas the tablet formulation is usually started at 5 mg or 10 mg, the drops allow for personalised titration to start at 1–5 drops (1–5 mg) per day for patients who may be particularly susceptible to adverse events with up-titration of 1 drop each day until the recommended starting dose of 10 mg has been reached. Vortioxetine has a clear dose-response and accumulating data indicate significantly better efficacy of the 20 mg dose if tolerated [6].

Like other antidepressants, the full antidepressant effect of vortioxetine develops over time and there has been concern that slower titration antidepressant schedules may induce delays in clinical response [3]. The aim of this pharmacokinetic modelling analysis was to understand the impact of the low and slow titration approach (start at 1 or 5 mg and increasing by 1 mg/day) with vortioxetine drops on the time taken to reach steady state plasma concentrations compared with standard titration schedules using IR-vortioxetine tablets.

Pharmacokinetic data for this modelling analysis were derived from an open-label, single-centre, single-dose crossover study in 26 healthy volunteers, which has been previously described [5]. Briefly, healthy adults aged 18–55 years were randomised 1:1 to receive a single dose of open-label vortioxetine 20 mg in a single IR tablet or 1 mL of oral drop solution. Tablets were ingested with 240 mL of water. The oral solution was administered directly into the participant’s mouth in a 1-mL syringe, followed by ingestion of 240 mL of water. Study drug was administered in the fasting state on Day 1, followed by washout until crossover on Day 29 and administration of the alternate formulation. Blood samples for pharmacokinetic assessments were drawn pre-dose and at 1, 2, 4, 6, 8, 10, 12, 16, 24, 36, 48 and 72 h post-dose.

Pharmacokinetic simulations were performed using a previously described population pharmacokinetic (popPK) model [7, 8]. The popPK model is a 2-compartment disposition model with first-order absorption and elimination and parameterized in terms of absorption rate (k_a), lag-time (ALAG), central volume of distribution (V2/F), oral clearance (CL/F), peripheral volume of distribution (V3/F) and inter-compartmental clearance (Q/F). Since bioequivalence between the tablet and drop formulations has been established [5], the same popPK model was used to simulate the plasma concentration-time profiles for the following dosing regimens:

1 mg (Day 1), 2 mg (Day 2), 3 mg (Day 3), 4 mg (Day 4), 5 mg (Day 5), 6 mg (Day 6), 7 mg (Day 7), 8 mg (Day 8), 9 mg (Day 9), 10 mg (Day 10-Day 20) with oral drops
5 mg (Day 1), 6 mg (Day 2), 7 mg (Day 3), 8 mg (Day 4), 9 mg (Day 5) and 10 mg (Day 6-Day 20) with oral drops
10 mg Day 1 – Day 20 with oral IR tablets
5 mg (Day 1 – Day7) and 10 mg (Day 8 – Day 20) with oral IR tablets

Simulations were performed with R (R Foundation for Statistical Computing, Vienna, Austria) and RStudio (RStudio, Inc., Boston, MA) using the package rxode2.

The simulated plasma concentration-time profiles are shown in Fig. 1. All dosing regimens approached 10 mg steady state concentrations within 2 weeks. Time to 5 or 10 mg plasma concentrations (defined as the first time the plasma concentration equalled the 5 or 10 mg steady-state concentration) were shortest for regimen C (1.2 days and 5.2 days, respectively) followed by B (3.1 and 7.3 days), and longer for regimens D (5.2 days and 10.3 days, respectively) and A (6.2 days and 11.2 days, respectively).

The time to reach full 10 mg steady-state, defined as the time when the trough (pre-dose) plasma concentration equalled the 10 mg steady state (upper dotted line in the figure) followed a similar pattern with regimen C having the shortest time to steady state (12 days), followed by regimen B (14 days), regimen D (17 days), and regimen A (18 days).

It is generally accepted that most oral antidepressants take between 2–4 weeks to see a full antidepressant effect [9, 10]. Results from this popPK modelling predict that a slow titration schedule starting at 5 mg with vortioxetine drops only delays the time to reach steady state 10 mg plasma concentrations by approximately 2 days compared with the standard starting dose of 10 mg with vortioxetine IR-tablets. Likewise, the time to reach steady state 10 mg concentrations with the most conservative regimen (regimen A, starting at 1 mg vortioxetine drops) was similar to the slower titration schedule with IR-tablets (starting at 5 mg vortioxetine IR-tablets) and well within the accepted time range of 2 weeks.

Given that there is significant interpatient variability in the time to reach steady state vortioxetine (the popPK model estimates that about half of patients treated reach steady state by Day 8 and 90% reach steady state by Day 12) [7] a 2-day delay in reaching steady state is not expected to be of significant clinical relevance and should be weighed against the potential beneficial effects on tolerability and adherence during titration. Recent real-world evidence with vortioxetine in Switzerland reported similar effectiveness of treatment for oral drops versus IR-tablets, with numerically higher response rates for the oral drops at 8 weeks. Interestingly, in this real-world study, whereas the starting dose was consistently lower for those treated with the drop formulation, the mean vortioxetine dose increased more rapidly, and patients tended to be titrated to higher doses (> 10 mg/day) earlier in the observation period than those who initiated treatment with IR-tablets [11]. Such observations support the idea that the titration schedule is not a key factor in effectiveness and that the ability to personalise the medication regimen may be helpful in enabling patients to reach the higher doses (15–20 mg) faster. In clinical practice, oral drops also offer a potential solution for patients who have difficulty or unwillingness to swallow rigid medications (e.g. due to physical or anxiety-related difficulties) [12] and in certain cases where the clinician wants to fine tune the dosing with granularity.

A key limitation of the analysis is that both the popPK model [7] and the bioequivalence study [5] were based on data from healthy individuals, which may not fully reflect the patient population. However, data in patients with MDD have previously confirmed utility of the 2-compartment model [8].

In summary, our data support the utility of vortioxetine drops in offering patients flexibility for personalised dosing titration without relevant impact on the time taken to reach steady state plasma concentrations.

Ethics approval

Not applicable

Consent for publication

Not applicable

Competing Interests

A. Fagiolini is/has been a consultant and/or a speaker and/or has received research grants from Angelini, Apsen, Boehringer Ingelheim, Daiichi Sankyo, Doc Generici, Italfarmaco, Janssen, Lundbeck, Mylan, Neuraxpharm, Otsuka, Pfizer, Recordati, Viatris and Vifor. E.H. Reines, A. Farovik, and J. Areberg are employees of H. Lundbeck A/S.

Funding

This work was funded by H Lundbeck A/S.

Author Contribution

AF was involved in the conception of the analyses, data interpretation, and critically reviewed the paper. EHR was involved in data interpretation and cowrote the first draft of the paper. AF was involved in data interpretation and critically reviewed the paper. JA conducted the analyses, was involved in data interpretation, and cowrote the first draft of the paper. All authors read and approved the final manuscript.

Acknowledgement

Medical writing assistance was provided by Anita Chadha-Patel of ACP Clinical Communications (Hertfordshire, UK) and was supported by H Lundbeck A/S.

Availability of data

Further data supporting the model are available upon reasonable request to the corresponding author.

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Fagiolini A, Adair M, Buchberg Petersen K, Areberg J, Christensen MC. Clinical benefits and bioequivalence of vortioxetine oral drop solution versus oral tablets. J Psychopharmacol. 2024;38(2):156–61.
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Competing interest reported. A. Fagiolini is/has been a consultant and/or a speaker and/or has received research grants from Angelini, Apsen, Boehringer Ingelheim, Daiichi Sankyo, Doc Generici, Italfarmaco, Janssen, Lundbeck, Mylan, Neuraxpharm, Otsuka, Pfizer, Recordati, Viatris and Vifor. E.H. Reines, A. Farovik, and J. Areberg are employees of H. Lundbeck A/S.

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You are reading this latest preprint version

Time to steady state with slow titration of vortioxetine drops versus oral tablets: a pharmacokinetic model

Status:

Journal Publication

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Abstract

Background

Methods

Results

Conclusions

Figures

Background

Methods

Results

Discussion

Conclusion

Declarations

Competing Interests

Funding

Author Contribution

Acknowledgement

Availability of data

References

Additional Declarations

Status:

Journal Publication

Version 1