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Cited by 228Advanced Drug Delivery SystemsHIV/AIDS drug development and treatmentHIV/AIDS Research and Interventions

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Development of an oral once-weekly drug delivery system for HIV antiretroviral therapy

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Kirtane, Ameya R., Abouzid, Omar, Minahan, Daniel, Bensel, Taylor, Hill, Alison L., Selinger, Christian, Bershteyn, Anna, Craig, Morgan, Mo, Shirley S., Mazdiyasni, Hormoz, Cleveland, Cody, Rogner, Jaimie, Lee, Young-Ah Lucy, Booth, Lucas, Javid, Farhad, Wu, Sarah J., Grant, Tyler, Bellinger, Andrew M., Nikolic, Boris, Hayward, Alison, Wood, Lowell, Eckhoff, Philip A., Nowak, Martin A., Langer, Robert, Traverso, Giovanni·2018·Nature Communications
DOI 10.1038/s41467-017-02294-6PMC PMC5760734
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Abstract

The efficacy of antiretroviral therapy is significantly compromised by medication non-adherence. Long-acting enteral systems that can ease the burden of daily adherence have not yet been developed. Here we describe an oral dosage form composed of distinct drug–polymer matrices which achieved week-long systemic drug levels of the antiretrovirals dolutegravir, rilpivirine and cabotegravir in a pig. Simulations of viral dynamics and patient adherence patterns indicate that such systems would significantly reduce therapeutic failures and epidemiological modelling suggests that using such an intervention prophylactically could avert hundreds of thousands of new HIV cases. In sum, weekly administration of long-acting antiretrovirals via a novel oral dosage form is a promising intervention to help control the HIV epidemic worldwide.

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Fig. 1 Concept of oral long acting antiretrovirals. a The design of the gastric resident dosage forms. The dosage form consists of an elastomeric core (grey) and six drug loaded arms (multi-coloured). b The cross section of the arm. The outer sleeve of the arms is made of a rigid structural polymer which provides the arm its mechanical strength. This sleeve is then filled with a drug–polymer matrix which releases the drug at a desired rate. c The manufacturing scheme of the dosage form. The expected performance of the dosage form in vivo is shown in d. The dosage form is loaded with three different polymers (blue, red and yellow) which release the drug at different rates. Selection of appropriate polymers may result in almost constant and sustained plasma drug concentrations. It should be noted that d is a schematic representing an ideal system, and is not experimentally obtained data
Fig. 1 Concept of oral long acting antiretrovirals. a The design of the gastric resident dosage forms. The dosage form consists of an elastomeric core (grey) and six drug loaded arms (multi-coloured). b The cross section of the arm. The outer sleeve of the arms is made of a rigid structural polymer which provides the arm its mechanical strength. This sleeve is then filled with a drug–polymer matrix which releases the drug at a desired rate. c The manufacturing scheme of the dosage form. The expected performance of the dosage form in vivo is shown in d. The dosage form is loaded with three different polymers (blue, red and yellow) which release the drug at different rates. Selection of appropriate polymers may result in almost constant and sustained plasma drug concentrations. It should be noted that d is a schematic representing an ideal system, and is not experimentally obtained dataCC BY · PubMed Central
Fig. 2 Mechanical characterization and gastric retention of gastric resident dosage forms. a The ultimate flexural stresses of various polymers were determined by using a 4-point bending test. Circles indicate individual measurements, and horizontal line indicates mean value. *p < 0.05, one-way ANOVA, post-hoc Bonferroni (comparing R6000 vs. PCL and PLA); #p < 0.05, two-sample t test. b The elastic moduli of candidate central elastomers were determined using tensile testing. Circles indicate individual measurements, and horizontal line indicates mean value. * indicates p < 0.05, N.S. indicates not significant, two-sample t test c The interface between candidate structural polymers and central elastomers was characterized by tensile testing. Circles indicate individual measurements, and horizontal line indicates mean value., *p < 0.05, one-way ANOVA, post-hoc Bonferroni (comparing R6000-1185 vs. each of the other groups); N.S. indicates not significant, two-sample t test. d Dosage forms made of Elastollan®1185 central elastomer and either PLA or Elastollan®R6000 arms were administered to pigs. Their integrity was analysed over time. Three dosage forms containing six arms each were tested. e Representative X-rays of dosage forms made of Elastollan®R6000 arms and Elastollan®1185 central elastomer in a pig immediately after deployment and on day 7. f Funnel testing of Elastollan®R6000-Elastollan®1185 dosage forms before dosing in pigs and after retrieval from pig stomach following 7-day residence. *indicates p < 0.05, paired two sample t test
Fig. 2 Mechanical characterization and gastric retention of gastric resident dosage forms. a The ultimate flexural stresses of various polymers were determined by using a 4-point bending test. Circles indicate individual measurements, and horizontal line indicates mean value. *p < 0.05, one-way ANOVA, post-hoc Bonferroni (comparing R6000 vs. PCL and PLA); #p < 0.05, two-sample t test. b The elastic moduli of candidate central elastomers were determined using tensile testing. Circles indicate individual measurements, and horizontal line indicates mean value. * indicates p < 0.05, N.S. indicates not significant, two-sample t test c The interface between candidate structural polymers and central elastomers was characterized by tensile testing. Circles indicate individual measurements, and horizontal line indicates mean value., *p < 0.05, one-way ANOVA, post-hoc Bonferroni (comparing R6000-1185 vs. each of the other groups); N.S. indicates not significant, two-sample t test. d Dosage forms made of Elastollan®1185 central elastomer and either PLA or Elastollan®R6000 arms were administered to pigs. Their integrity was analysed over time. Three dosage forms containing six arms each were tested. e Representative X-rays of dosage forms made of Elastollan®R6000 arms and Elastollan®1185 central elastomer in a pig immediately after deployment and on day 7. f Funnel testing of Elastollan®R6000-Elastollan®1185 dosage forms before dosing in pigs and after retrieval from pig stomach following 7-day residence. *indicates p < 0.05, paired two sample t testCC BY · PubMed Central
Fig. 3 Assessment of drug stability and release rates from different polymer matrices. a Different antiretroviral drugs were incubated in SGF for 24 h at 37 °C. At various times, drug concentration in SGF was measured using HPLC. b Stability of various drugs upon incubation at 150 °C for 2 h was assessed using HPLC. Circles represent individual data points and horizontal lines indicate mean value. Release of DTG (c), RPV (d) and CAB (e) from various polymer matrices in SGF was measured using HPLC. Polymer matrices from left to right are: poly(ethylene glycol) + Kollidon VA64, poly(adipic anhydride), poly(sebacic anhydride) and poly(caprolactone). Circles are individual data points, and lines represent mean release profile
Fig. 3 Assessment of drug stability and release rates from different polymer matrices. a Different antiretroviral drugs were incubated in SGF for 24 h at 37 °C. At various times, drug concentration in SGF was measured using HPLC. b Stability of various drugs upon incubation at 150 °C for 2 h was assessed using HPLC. Circles represent individual data points and horizontal lines indicate mean value. Release of DTG (c), RPV (d) and CAB (e) from various polymer matrices in SGF was measured using HPLC. Polymer matrices from left to right are: poly(ethylene glycol) + Kollidon VA64, poly(adipic anhydride), poly(sebacic anhydride) and poly(caprolactone). Circles are individual data points, and lines represent mean release profileCC BY · PubMed Central
Fig. 4 Plasma pharmacokinetics of immediate release and sustained release antiretrovirals. The concentration time profiles of (a) DTG immediate release (b), DTG sustained release (c), RPV immediate release (d), RPV sustained release (e), CAB immediate release and (f) CAB sustained release are shown. Each dosage form was tested in three animals, and plasma samples from each animal were processed three times. Data was first averaged within each animal (shown by the grey lines) and then between animals in each treatment group (shown by the black line). *indicates p < 0.05, two sample t test comparing sustained release formulations and immediate release formulations at matching time points
Fig. 4 Plasma pharmacokinetics of immediate release and sustained release antiretrovirals. The concentration time profiles of (a) DTG immediate release (b), DTG sustained release (c), RPV immediate release (d), RPV sustained release (e), CAB immediate release and (f) CAB sustained release are shown. Each dosage form was tested in three animals, and plasma samples from each animal were processed three times. Data was first averaged within each animal (shown by the grey lines) and then between animals in each treatment group (shown by the black line). *indicates p < 0.05, two sample t test comparing sustained release formulations and immediate release formulations at matching time pointsCC BY · PubMed Central
Fig. 5 Mathematical modelling of HIV treatment outcomes using long-acting antiretrovirals. a–h Viral dynamics modelling of HIV growth and evolution within individual patients. We consider a hypothetical weekly formulation, with identical peak concentration and 7-fold longer half-life a. Adherence patterns described in more detail in text and Supplementary Information. Patients are initially fully virologically-suppressed and failure is defined as two consecutive monthly viral load measurements > 200 c/mL in the year-long follow-up period. The height of the shaded area indicates the probability of outcome. Predicted patient outcomes versus adherence level (% of scheduled doses taken) for existing daily formulation of DTG (c) and RPV (f), and for long-acting versions, (d, g). Predicted outcomes for DTG (e) and RPV (h): a cohort of patients with a distribution of adherence levels taken from empirical data11, average adherence ~70% (b). C max is the peak drug level and is determined by the dosage size and absorption. 100% means that this value is the same for the hypothetical long-acting formulation as the existing one. i–j Epidemiological modelling of the impact of using oral long-acting antiretrovirals for PrEP in South Africa. The contours show the cumulative number of additional infections prevented (in thousands) by switching from daily to weekly oral PrEP formulation in South Africa by 2037. The x-axis depicts the supposed increase in efficacy (defined as reduction in per-exposure probability of infection), compared to a baseline efficacy of 50%. Solid lines indicating the plausible estimates (confidence intervals depicted as dashed lines) from meta-analyses respectively. The y-axis shows assumed increase in coverage (% of high-risk population receiving PrEP) assuming a baseline coverage of 30%. “Pessimistic ART” assumes current rates of ART use for treatment (i) while “Achieve 90-90-90” assumes increased rates (j)
Fig. 5 Mathematical modelling of HIV treatment outcomes using long-acting antiretrovirals. a–h Viral dynamics modelling of HIV growth and evolution within individual patients. We consider a hypothetical weekly formulation, with identical peak concentration and 7-fold longer half-life a. Adherence patterns described in more detail in text and Supplementary Information. Patients are initially fully virologically-suppressed and failure is defined as two consecutive monthly viral load measurements > 200 c/mL in the year-long follow-up period. The height of the shaded area indicates the probability of outcome. Predicted patient outcomes versus adherence level (% of scheduled doses taken) for existing daily formulation of DTG (c) and RPV (f), and for long-acting versions, (d, g). Predicted outcomes for DTG (e) and RPV (h): a cohort of patients with a distribution of adherence levels taken from empirical data11, average adherence ~70% (b). C max is the peak drug level and is determined by the dosage size and absorption. 100% means that this value is the same for the hypothetical long-acting formulation as the existing one. i–j Epidemiological modelling of the impact of using oral long-acting antiretrovirals for PrEP in South Africa. The contours show the cumulative number of additional infections prevented (in thousands) by switching from daily to weekly oral PrEP formulation in South Africa by 2037. The x-axis depicts the supposed increase in efficacy (defined as reduction in per-exposure probability of infection), compared to a baseline efficacy of 50%. Solid lines indicating the plausible estimates (confidence intervals depicted as dashed lines) from meta-analyses respectively. The y-axis shows assumed increase in coverage (% of high-risk population receiving PrEP) assuming a baseline coverage of 30%. “Pessimistic ART” assumes current rates of ART use for treatment (i) while “Achieve 90-90-90” assumes increased rates (j)CC BY · PubMed Central

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Research works printed but not linked: 2

  1. Andrew Owen et al. Human confirmation of oral dose reduction potential of nanoparticle ARV formulations. Conference on Retroviruses and Opportunistic Infections, abstr. 39 (2017).
  2. Wijting I. et al. Dolutegravir as maintenance monotherapy for HIV-1: a randomized clinical trial. Conference on Retroviruses and Opportunistic Infections, abstr. 451LB (2017).

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Metadata

Authors
Kirtane, A. R., Abouzid, O., Minahan, D., Bensel, T., Hill, A. L., Selinger, C., Bershteyn, A., Craig, M., Mo, S. S., Mazdiyasni, H., Cleveland, C., Rogner, J., Lee, Y.-A. L., Booth, L., Javid, F., Wu, S. J., Grant, T., Bellinger, A. M., Nikolic, B., Hayward, A., Wood, L., Eckhoff, P. A., Nowak, M. A., Langer, R., & Traverso, G.
Affiliations
  • Koch Institute for Integrative Cancer Research At MIT (US)
  • Harvard University (US)
  • Institute for Disease Modeling (US)
  • Brigham and Women's Hospital (US)
  • Massachusetts Institute of Technology (US)
  • Lyndra Therapeutics (United States) (US)
Corresponding author
Traverso, Giovanni
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2018-01-09
Volume
9
Issue
1
Pages
2-2
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-017-02294-6
PMC
PMC5760734
OpenAlex
W2781350987
Cited by
227
References
77
Citations by year
2026: 8 · 2025: 19 · 2024: 16 · 2023: 30 · 2022: 23 · 2021: 38 · 2020: 43 · 2019: 28 · 2018: 22
FWCI
13.14
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
Funders
  • Bill and Melinda Gates Foundation (OPP1139937, OPP1139921, OPP1148627)
  • Brigham and Women's Hospital
  • National Institutes of Health (DP5OD019851, 4r37eb000244-34, EB-000244)
  • National Institute of Allergy and Infectious Diseases (R01AI131416, P30AI060354)
  • National Institute of Biomedical Imaging and Bioengineering (R01EB000244, R37-EB000244)
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
  • Health Sciences › Medicine › Infectious Diseases › HIV/AIDS drug development and treatment
  • Health Sciences › Medicine › Infectious Diseases › HIV/AIDS Research and Interventions
Keywords
HIV antiretroviral therapy, long-acting drug delivery, oral dosage forms, dolutegravir, rilpivirine, cabotegravir, medication adherence, viral dynamics, HIV prevention, prophylaxis, porcine model
MeSH terms
Rilpivirine, Proof of Concept Study, Dolutegravir, Administration, Oral, Animals, Drug Evaluation, Preclinical, Heterocyclic Compounds, 3-Ring, Humans, Models, Theoretical, Oxazines, Patient Compliance, Piperazines, Pyridones, Swine, Drug Delivery Systems, Anti-HIV Agents, Diketopiperazines

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