Why are multiple courses of isotretinoin necessary to treat acne?

Question

The following guidances don't detail why multiple courses are more efficacious?

Aug 21 2019 PRODUCT MONOGRAPH on Accutane, Hoffmann-La Roche Limited, p. 13 of 36.

Effects of multiple courses of Accutane on the developing musculoskeletal system are unknown. There is some evidence that long-term, high-dose, or multiple courses of therapy with isotretinoin have more of an effect than a single course of therapy on the musculoskeletal system.

3 doctors also allege the efficacy in multiple courses of Epuris.

The therapeutic response to isotretinoin is dose-related and varies between patients. This necessitates individual adjustment of dosage according to the response of the condition and the patient’s tolerance of the drug. In most cases, complete or near-complete suppression of acne is achieved with a single 12 to 16 week course of therapy. If a second course of therapy is needed, it can be initiated eight or more weeks after completion of the first course, since experience has shown that patients may continue to improve while off the drug.

Answer 1

To clarify the block quotes you posted, muscle soreness is a rare negative side effect of isotretinoin. It is believed that the effects of isotretinoin depend on the cumulative dose you have received (so, a high dose for a shorter period of time would be similar to a low dose for a longer period of time). The first block quote you are asking about is saying that the potentially negative effects on the musculoskeletal system are thought to be dependent on the cumulative dose, just like the positive effects on acne (so, longer courses, higher doses, and multiple courses all have increased effect because they result in higher cumulative doses).

The second block quote you are wondering about is saying that some people require more of the drug than others to achieve remission of their acne, and they recommend waiting 8 weeks between courses so that the body completes the first course of the drug, which they say may take 8 weeks after the final dose is taken.

As far as why cumulative dose is the target ... from what I've read, that's just what was found in the clinical trials when the drug was being investigated. It appears that some researchers think the story is more complex than just cumulative dose, but that is what is used because that is what the clinical trials showed was most important in preventing relapse in real patients.

Layton AM, Cunliffe WJ. Guidelines for optimal use of isotretinoin in acne. J Am Acad Dermatol. 1992;27(6 Pt 2):S2-7.

Rademaker M. Making sense of the effects of the cumulative dose of isotretinoin in acne vulgaris. Int J Dermatol. 2016;55(5):518-23.

I hope this helps.